HRK; harakiri, BCL2 interacting protein (12q24.22)

Gene Summary

Gene:HRK; harakiri, BCL2 interacting protein
Aliases: DP5, HARAKIRI
Summary:This gene encodes a member of the BCL-2 protein family. Members of this family are involved in activating or inhibiting apoptosis. The encoded protein localizes to intracellular membranes. This protein promotes apoptosis by interacting with the apoptotic inhibitors BCL-2 and BCL-X(L) via its BH3 domain. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:activator of apoptosis harakiri
Updated:15 December, 2014


What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 15 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cell Survival
  • Lymphoma
  • BAK1
  • Cancer Gene Expression Regulation
  • Gene Knockdown Techniques
  • Chromosomes, Human, Pair None
  • Stress, Physiological
  • Apoptosis
  • Tumor Suppressor Protein p14ARF
  • Diffuse Large B-Cell Lymphoma
  • BCL2 protein
  • Survival Rate
  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • Breast Cancer
  • Oligonucleotide Array Sequence Analysis
  • Prostate Cancer
  • DNA Methylation
  • Ovarian Cancer
  • Up-Regulation
  • Promoter Regions
  • Neoplasm Proteins
  • BID
  • Immunohistochemistry
  • Transfection
  • Glioblastoma
  • Cancer DNA
  • Turkey
  • Loss of Heterozygosity
  • Polymerase Chain Reaction
  • Messenger RNA
  • CpG Islands
  • Epigenetics
  • Proto-Oncogene Proteins
  • Signal Transduction
  • Genetic Therapy
  • p53 Protein
  • Tumor Markers
  • bcl-2-Associated X Protein
Tag cloud generated 15 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Prostate CancerHRK and Prostate Cancer View Publications4
Breast CancerHRK and Breast Cancer View Publications3
-HRK and Diffuse Large B-Cell Lymphoma View Publications3
Ovarian CancerHRK and Ovarian Cancer View Publications2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: HRK (cancer-related)

Kaku Y, Nagaya H, Tsuchiya A, et al.
Newly synthesized anticancer drug HUHS1015 is effective on malignant pleural mesothelioma.
Cancer Sci. 2014; 105(7):883-9 [PubMed] Related Publications
The newly synthesized naftopidil analogue HUHS1015 reduced cell viability in malignant pleural mesothelioma cell lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452, with the potential greater than that for the anticancer drugs paclitaxel or cisplatin at concentrations higher than 30 μM. HUHS1015 induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. HUHS1015 upregulated expression of mRNAs for Puma, Hrk, and Noxa in MSTO-211H and NCI-H2052 cells, suggesting HUHS1015-induced mitochondrial apoptosis. HUHS1015 clearly suppressed tumor growth in mice inoculated with NCI-H2052 cells. Taken together, the results of the present study indicate that HUHS1015 could be developed as an effective anticancer drug for treatment of malignant pleural mesothelioma.

Related: Apoptosis Lung Cancer Mesothelioma PMAIP1

Akay OM, Aras BD, Isiksoy S, et al.
BCL2, BCL6, IGH, TP53, and MYC protein expression and gene rearrangements as prognostic markers in diffuse large B-cell lymphoma: a study of 44 Turkish patients.
Cancer Genet. 2014; 207(3):87-93 [PubMed] Related Publications
The purpose of this study was to determine the frequency of BCL2, BCL6, IGH, TP53, and MYC protein expression and rearrangements of the respective genes in diffuse large B-cell lymphoma (DLBCL) patients and to assess their prognostic values. Samples from 44 patients with DLBCL were evaluated using fluorescence in situ hybridization and immunohistochemical analyses. BCL6 was the most rearranged gene (63.6%), followed by MYC (31.8%), TP53 (22.7%), and BCL2 (18.2%). Multiple rearrangements were detected in 40.9% of the cases. BCL6 was the most expressed protein (78.6%), followed by TP53 (69.04%), BCL2 (59.5%) and MYC (14.3%). Expression of multiple proteins was detected in 67.4% of the cases. BCL2 (P = .003) expression had a significant negative influence on overall survival,whereas BCL6 (P = .014) expression had a significant positive influence. Our results with a different pattern of gene rearrangements and associated protein overexpression indicate the molecular genetic complexity of DLBCLs, which reflects the morphologic, biologic, and clinical heterogeneity of these lymphomas.

Related: TP53 BCL6

Chung J, Karkhanis V, Tae S, et al.
Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing.
J Biol Chem. 2013; 288(49):35534-47 [PubMed] Free Access to Full Article Related Publications
Epigenetic regulation mediated by lysine- and arginine-specific enzymes plays an essential role in tumorigenesis, and enhanced expression of the type II protein arginine methyltransferase PRMT5 as well as the polycomb repressor complex PRC2 has been associated with increased cell proliferation and survival. Here, we show that PRMT5 is overexpressed in three different types of non-Hodgkin lymphoma cell lines and clinical samples as well as in mouse primary lymphoma cells and that it up-regulates PRC2 expression through inactivation of the retinoblastoma proteins RB1 and RBL2. Although PRMT5 epigenetically controls RBL2 expression, it indirectly promotes RB1 phosphorylation through enhanced cyclin D1 expression. Furthermore, we demonstrate that PRMT5 knockdown in non-Hodgkin lymphoma cell lines and mouse primary lymphoma cells leads to RBL2 derepression and RB1 reactivation, which in turn inhibit PRC2 expression and trigger derepression of its CASP10, DAP1, HOXA5, and HRK pro-apoptotic target genes. We also show that reduced PRMT5 expression leads to cyclin D1 transcriptional repression via loss of TP53K372 methylation, which results in decreased BCL3 expression and enhanced recruitment of NF-κB p52-HDAC1 repressor complexes to the cyclin D1 promoter. These findings indicate that PRMT5 is a master epigenetic regulator that governs expression of its own target genes and those regulated by PRC2 and that its inhibition could offer a promising therapeutic strategy for lymphoma patients.

Related: Non Hodgkin's Lymphoma RB1 Signal Transduction BCL1 Gene (CCND1)

Chen L, Monti S, Juszczynski P, et al.
SYK inhibition modulates distinct PI3K/AKT- dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas.
Cancer Cell. 2013; 23(6):826-38 [PubMed] Free Access to Full Article Related Publications
B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large B cell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-κB. In previous studies, chemical SYK blockade selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCLs. Herein, we characterize distinct SYK/PI3K-dependent survival pathways in DLBCLs with high or low baseline NF-κB activity including selective repression of the pro-apoptotic HRK protein in NF-κB-low tumors. We also define SYK/PI3K-dependent cholesterol biosynthesis as a feed-forward mechanism of maintaining the integrity of BCRs in lipid rafts in DLBCLs with low or high NF-κB. In addition, SYK amplification and PTEN deletion are identified as selective genetic alterations in primary "BCR"-type DLBCLs.

Related: Apoptosis AKT1 Signal Transduction FOXO1A gene

Willimott S, Beck D, Ahearne MJ, et al.
Cap-translation inhibitor, 4EGI-1, restores sensitivity to ABT-737 apoptosis through cap-dependent and -independent mechanisms in chronic lymphocytic leukemia.
Clin Cancer Res. 2013; 19(12):3212-23 [PubMed] Related Publications
PURPOSE: The lymph node microenvironment promotes resistance to chemotherapy in chronic lymphocytic leukemia (CLL), partly through induction of BCL2 family prosurvival proteins. Currently available inhibitors do not target all BCL2 family prosurvival proteins and their effectiveness is also modified by proapoptotic BCL2 homology domain 3 (BH3) only protein expression. The goal of this study was to evaluate synergy between the eIF4E/eIF4G interaction inhibitor, 4EGI-1, and the BH3 mimetic, ABT-737.
EXPERIMENTAL DESIGN: CLL cells were cultured in conditions to mimic the lymph node microenvironment. Protein synthesis and cap-complex formation were determined. Polysome association of mRNAs from BCL2 family survival genes was analyzed by translational profiling. The effects of 4EGI-1 and the BCL2/BCL2L1 antagonist, ABT-737, on CLL cell apoptosis were determined.
RESULTS: Protein synthesis was increased approximately 6-fold by stromal cell/CD154 culture in a phosphoinositide 3-kinase α (PI3Kα)-specific manner and was reduced by 4EGI-1. PI3K inhibitors and 4EGI-1 also reduced cap-complex formation but only 4EGI-1 consistently reduced BCL2L1 and BCL2A1 protein levels. 4EGI-1, but not PI3K inhibitors or rapamycin, induced an endoplasmic reticulum stress response including proapoptotic NOXA and the translation inhibitor phosphorylated eIF2α. 4EGI-1 and ABT-737 synergized to cause apoptosis, independent of levels of prosurvival protein expression in individual patients.
CONCLUSIONS: Overall protein synthesis and cap-complex formation are induced by microenvironment stimuli in CLL. Inhibition of the cap-complex was not sufficient to repress BCL2 family prosurvival expression, but 4EGI-1 inhibited BCL2A1 and BCL2L1 while inducing NOXA through cap-dependent and -independent mechanisms. 4EGI-1 and ABT-737 synergized to produce apoptosis, and these agents may be the basis for a therapeutically useful combination.

Related: Apoptosis Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Chang I, Majid S, Saini S, et al.
Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells.
Mol Cancer Ther. 2013; 12(6):1049-59 [PubMed] Related Publications
Prostate cancer is one of the most prevalent cancers in males and ranks as the second most common cause of cancer-related deaths. 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, is a promising anticancer agent for various types of cancers. Although 2-ME has been shown to activate c-Jun-NH2-kinase (JNK) and mitochondrial-dependent apoptotic signaling pathways, the underlying mechanisms, including downstream effectors, remain unclear. Here, we report that the human Bcl-2 homology 3 (BH3)-only protein harakiri (Hrk) is a critical effector of 2-ME-induced JNK/mitochondria-dependent apoptosis in prostate cancer cells. Hrk mRNA and protein are preferentially upregulated by 2-ME, and Hrk induction is dependent on the JNK activation of c-Jun. Hrk knockdown prevents 2-ME-mediated apoptosis by attenuating the decrease in mitochondrial membrane potential, subsequent cytochrome c (cyt c) release, and caspase activation. Involvement of the proapoptotic protein Bak in this process suggested the possible interaction between Hrk and Bak. Thus, Hrk activation by 2-ME or its overexpression displaced Bak from the complex with antiapoptotic protein Bcl-xL, whereas deletion of the Hrk BH3 domain abolished its interaction with Bcl-xL, reducing the proapoptotic function of Hrk. Finally, Hrk is also involved in the 2-ME-mediated reduction of X-linked inhibitor of apoptosis through Bak activation in prostate cancer cells. Together, our findings suggest that induction of the BH3-only protein Hrk is a critical step in 2-ME activation of the JNK-induced apoptotic pathway, targeting mitochondria by liberating proapoptotic protein Bak.

Related: Apoptosis MAP2K4 gene Mitochondrial Mutations in Cancer Prostate Cancer Signal Transduction BAK1

Xu M, Chen X, Chen N, et al.
Synergistic silencing by promoter methylation and reduced AP-2α transactivation of the proapoptotic HRK gene confers apoptosis resistance and enhanced tumor growth.
Am J Pathol. 2013; 182(1):84-95 [PubMed] Related Publications
The Harakiri (HRK) gene encodes an important proapoptotic mitochondrial protein of the Bcl-2 family. HRK is expressed in normal tissues but is decreased in many cancers such as melanoma, the mechanisms of which have not been fully elucidated. Here, we demonstrate that HRK is silenced by hypermethylation of a major proximal CpG island in the HRK promoter. Furthermore, we show that HRK is a novel target gene regulated by the transcription factor AP-2α, which interacts with an AP-2α binding site in the HRK promoter. Hypermethylation of the major proximal CpG island (which contains the AP-2α binding site within the most densely methylated -218- to -194-bp region) inhibited AP-2α binding and transcriptional activity. Artificial overexpression of AP-2α in melanoma cells up-regulated HRK transcription, which was further restored by treatment with DNA methyltransferase inhibitor 5-azacytidine. Artificial overexpression of HRK by recombinant adenovirus induced caspase-dependent apoptosis, inhibited melanoma cell growth in vitro, and markedly reduced in vivo melanoma growth in a nude mouse xenograft model. RNA interference by siHRK or siAP-2α reversed the above effects. We conclude that the synergistic effects of HRK promoter hypermethylation and loss of AP-2α transactivation lead to HRK gene silencing and confer resistance to apoptosis and enhanced tumor growth. These novel molecular lesions may provide the basis for new therapeutic approaches to treating AP-2α- and HRK-deficient cancers.

Related: Apoptosis Melanoma Cancer Prevention and Risk Reduction TFAP2A

Cartron PF, Loussouarn D, Campone M, et al.
Prognostic impact of the expression/phosphorylation of the BH3-only proteins of the BCL-2 family in glioblastoma multiforme.
Cell Death Dis. 2012; 3:e421 [PubMed] Free Access to Full Article Related Publications
Apoptosis has a crucial role in anti-cancer treatment. The proteins of the BCL-2 family are core members of the apoptotic program. Thus, we postulated that alterations in the expression of BCL-2 protein family, and in particular in that of the Bcl-2 homology domain 3 (BH3)-only proteins (which can neutralized anti-apoptotic proteins or activate pro-apoptotic proteins) could account for differences in the overall survival (OS) of patients. To test this hypothesis, we analyzed the expression of 15 members of the BCL-2 protein family (Bax, Bak, Bok, Bcl-2, Bcl-xl, Bcl-w, Mcl-1, Bad, Bid, Bim, Bik, Bmf, Hrk, Noxa and Puma) in glioblastoma multiforme (GBM) tumors, the most frequent brain tumor in adults. We found that none of the individual expression of these proteins is associated with a significant variation in OS of the patients. However, when all BH3 proteins were pooled to determine a BH3(score), this score was significantly correlated with OS of GBM patients. We also noted that patients with a have high level of phospho-Bad and phospho-Bim displayed a lower OS. Thus, BH3 scoring/profiling could be used as an independent prognostic factor in GBM when globally analyzed.

Related: BID

Pike LR, Phadwal K, Simon AK, Harris AL
ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia.
Mol Biol Rep. 2012; 39(12):10811-22 [PubMed] Related Publications
Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.

Related: Breast Cancer PMAIP1

Pyrzynska B, Banach-Orlowska M, Teperek-Tkacz M, et al.
Multifunctional protein APPL2 contributes to survival of human glioma cells.
Mol Oncol. 2013; 7(1):67-84 [PubMed] Free Access to Full Article Related Publications
Some endocytic proteins have recently been shown to play a role in tumorigenesis. In this study, we demonstrate that APPL2, an adapter protein with known endocytic functions, is upregulated in 40% cases of glioblastoma multiforme, the most common and aggressive cancer of the central nervous system. The silencing of APPL2 expression by small interfering RNAs (siRNAs) in glioma cells markedly reduces cell survival under conditions of low growth factor availability and enhances apoptosis (measured by executor caspase activity). Long-term depletion of APPL2 by short hairpin RNAs (shRNAs), under regular growth factor availability, suppresses the cell transformation abilities, assessed by inhibited colony formation in soft agar and by reduced xenograft tumor growth in vivo. At the molecular level, the negative effect of APPL2 knockdown on cell survival is not due to the alterations in AKT or GSK3β activities which were reported to be modulated by APPL proteins. Instead, we attribute the reduced cell survival upon APPL2 depletion to the changes in gene expression, in particular to the upregulation of apoptosis-related genes, such as UNC5B (a proapoptotic dependence receptor) and HRK (harakiri, an activator of apoptosis, which antagonizes anti-apoptotic function of Bcl2). In support of this notion, the loss of glioma cell survival upon APPL2 knockdown can be rescued either by an excess of netrin-1, the prosurvival ligand of UNC5B or by simultaneous silencing of HRK. Consistently, APPL2 overexpression reduces expression of HRK and caspase activation in cells treated with apoptosis inducers, resulting in the enhancement of cell viability. This prosurvival activity of APPL2 is independent of its endosomal localization. Cumulatively, our data indicate that a high level of APPL2 protein might enhance glioblastoma growth by maintaining low expression level of genes responsible for cell death induction.

Related: Apoptosis

Li H, Cai Q, Wu H, et al.
SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK.
Mol Cancer Res. 2012; 10(11):1462-72 [PubMed] Free Access to Full Article Related Publications
Epithelial ovarian cancer (EOC) ranks first as the cause of death for gynecological cancers in the United States. SUZ12 is a component of the polycomb repressive complex 2 (PRC2) and is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). The role of SUZ12 in EOC has never been investigated. Here, we show that SUZ12 is expressed at significantly higher levels in human EOC (n = 117) compared with either normal human ovarian surface epithelium (n = 35, P < 0.001) or fallopian tube epithelium (n = 15, P < 0.001). There is a positive correlation between expression of SUZ12 and EZH2 in human EOC (P < 0.001). In addition, expression of SUZ12 positively correlates with Ki67, a marker of cell proliferation (P < 0.001), and predicts shorter overall survival (P = 0.0078). Notably, knockdown of SUZ12 suppresses the growth of human EOC cells in vitro and in vivo in both orthotopic and subcutaneous xenograft EOC models. In addition, SUZ12 knockdown decreases the levels of H3K27Me3 and triggers apoptosis of human EOC cells. Mechanistically, we identified Harakiri (HRK), a proapoptotic gene, as a novel SUZ12 target gene, and showed that HRK upregulation mediates apoptosis induced by SUZ12 knockdown in human EOC cells. In summary, we show that SUZ12 promotes the proliferation of human EOC cells by inhibiting apoptosis and HRK is a novel SUZ12 target gene whose upregulation contributes to apoptosis induced by SUZ12 knockdown.

Related: Apoptosis MKI67 Ovarian Cancer

Dimberg LY, Dimberg A, Ivarsson K, et al.
Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma.
BMC Cancer. 2012; 12:318 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM.
METHODS: To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS).
RESULTS: To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered.
CONCLUSION: We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.

Related: TNFRSF6 gene Apoptosis Myeloma Myeloma - Molecular Biology

Tvrdík D, Skálová H, Dundr P, et al.
Apoptosis - associated genes and their role in predicting responses to neoadjuvant breast cancer treatment.
Med Sci Monit. 2012; 18(1):BR60-67 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Neoadjuvant chemotherapy is used in the treatment of breast carcinoma because it substantially reduces the size of the primary tumor and lymph node metastases. The present study investigated biomarkers that can predict a pathologic response to the therapy.
MATERIAL/METHODS: The role of apoptosis in regression of the tumors after neoadjuvant chemotherapy was determined by TUNEL and anti-active caspase 3 assay. The transcriptional profile of 84 key apoptosis genes was evaluated in both pre-therapeutically obtained tumor tissue by core needle biopsy and in specimens removed by final surgery, using a pathway-specific real-time PCR assay. Obtained data were analyzed by hierarchical cluster analysis and correlation analysis. The immunohistochemical profile of each tumor was determined using the standard ABC method.
RESULTS: On the basis of a hierarchical cluster analysis of 13 significantly changed genes, we divided patients into good and poor prognosis groups, which correlate well with progression-free survival. In the good prognosis group, we found a statistically significant down-regulation of the expression of MCL1 and IGF1R genes after neoadjuvant treatment. We also found a statistically significant overexpression of BCL2L10, BCL2AF1, CASP8, CASP10, CASP14, CIDEB, FADD, HRK, TNFRSF25, TNFSF8 and CD70 genes. In contrast, we found up-regulation of IGF1R after the treatment in the group with poor prognosis.
CONCLUSIONS: Gene expression profiling using real-time PCR assay is a valuable research tool for the investigation of molecular markers, which reflect tumor biology and treatment response.

Related: Apoptosis Breast Cancer

Le XF, Mao W, Lu Z, et al.
Dasatinib induces autophagic cell death in human ovarian cancer.
Cancer. 2010; 116(21):4980-90 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dasatinib, an inhibitor of Src/Abl family kinases, can inhibit tumor growth of several solid tumors. However, the effect and mechanism of action of dasatinib in human ovarian cancer cells remains unknown.
METHODS: Dasatinib-induced autophagy was determined by acridine orange staining, punctate localization of GFP-LC3, LC3 protein blotting, and electron microscopy. Significance of beclin 1, AKT, and Bcl-2 in dasatinib-induced autophagy and growth inhibition was assayed by small interfering RNA (siRNA) silencing and/or overexpression of the gene of interest.
RESULTS: Dasatinib inhibited cell growth by inducing little apoptosis, but substantial autophagy in SKOv3 and HEY ovarian cancer cells. In vivo studies showed dasatinib inhibited tumor growth and induced both autophagy and apoptosis in a HEY xenograft model. Knockdown of beclin 1 and Atg12 expression with their respective siRNAs diminished dasatinib-induced autophagy, whereas knockdown of p27Kip1 with specific siRNAs did not. Small hairpin RNA knockdown of beclin 1 expression reduced dasatinib-induced autophagy and growth inhibition. Dasatinib reduced the phosphorylation of AKT, mTOR, p70S6K, and S6 kinase expression. Constitutive expression of AKT1 and AKT2 inhibited dasatinib-induced autophagy in both HEY and SKOv3 cells. Dasatinib also reduced Bcl-2 expression and activity. Overexpression of Bcl-2 partially prevented dasatinib-induced autophagy.
CONCLUSIONS: Dasatinib induces autophagic cell death in ovarian cancer that partially depends on beclin 1, AKT, and Bcl-2. These results may have implications for clinical use of dasatinib.

Related: Apoptosis Ovarian Cancer AKT1 Dasatinib (Sprycel)

Kater B, Hunold A, Schmalz HG, et al.
Iron containing anti-tumoral agents: unexpected apoptosis-inducing activity of a ferrocene amino acid derivative.
J Cancer Res Clin Oncol. 2011; 137(4):639-49 [PubMed] Related Publications
PURPOSE: Due to the severe problems accompanied with multiple drug resistance (MDR), agents that can induce apoptosis independently of death-suppressing proteins are required. Here, we show that the ferrocene derivative HUNI 068 is active against cancer cells and overcomes different mechanisms of multiple drug resistance (MDR).
METHODS: Proliferation inhibition was determined by using a CASY(®)CellCounter. DNA fragmentation assay and annexin-V/PI binding assays measured apoptosis, and necrosis was excluded by LDH-release assay. Drug-resistant cell lines were generated to test the ability to overcome MDR. By real-time PCR, alterations in gene expression of treated cells were analyzed. The apoptosis pathway was investigated by immunoblotting and measurement of mitochondrial membrane permeability transition.
RESULTS: HUNI 068 leads to proliferation inhibition and apoptosis mediation, but only minimal necrosis induction. Healthy leukocytes seem to be less affected than cancer cells. The compound overcomes drug resistance to vincristine and daunorubicin. Independence of p-glycoprotein and Bcl-2 overexpression is probable, and upregulation of the anti-Bcl-2 protein harakiri was seen. Combined treatment with vincristine leads to synergistic effects. In different primary tumor cells, HUNI 068 achieved acceptable effects where tolerance to some conventional drugs was shown. Induction of apoptosis is FADD-independent, but associated with a reduced mitochondrial membrane potential and activation of caspase-9, indicating the intrinsic apoptosis pathway via mitochondria.
CONCLUSIONS: HUNI 068 is a promising new compound with activity even against MDR tumor cells. Further investigations into the class of ferrocene-derived agents might reveal compounds with improved activity for a more specific and safe anti-cancer therapy.

Related: Apoptosis Leukemia Vincristine

Suvasini R, Somasundaram K
Essential role of PI3-kinase pathway in p53-mediated transcription: Implications in cancer chemotherapy.
Oncogene. 2010; 29(25):3605-18 [PubMed] Related Publications
The PI3-kinase pathway is the target of inactivation in achieving better cancer chemotherapy. Here, we report that p53-mediated transcription is inhibited by pharmacological inhibitors and a dominant-negative mutant of PI3-kinase, and this inhibition was relieved by a constitutively active mutant of PI3-kinase. Akt/PKB and mTOR, the downstream effectors of PI3-kinase, were also found to be essential. LY294002 (PI3-kinase inhibitor) pre-treatment altered the post-translational modifications and the sub-cellular localization of p53. Although LY294002 increased the chemosensitivity of cells to low concentrations of adriamycin (adriamycin-low), it protected the cells from cytotoxicity induced by high concentrations of adriamycin (adriamycin-high) in a p53-dependent manner. Further, we found that LY294002 completely abolished the activation of p53 target genes (particularly pro-apoptotic) under adriamycin-high conditions, whereas it only marginally repressed the p53 target genes under adriamycin-low conditions; in fact, it further activated the transcription of NOXA, HRK, APAF1 and CASP5 genes. Thus, the differential effect of PI3-kinase on p53 functions seems to be responsible for the differential regulation of DNA damage-induced cytotoxicity and cell death by PI3-kinase. Our finding becomes relevant in the light of ongoing combination chemotherapy trials with the PI3-kinase pathway inhibitors and underscores the importance of p53 status in the careful formulation of combination chemotherapies.

Related: Doxorubicin Cancer Prevention and Risk Reduction Signal Transduction TP53

Hervouet E, Vallette FM, Cartron PF
Impact of the DNA methyltransferases expression on the methylation status of apoptosis-associated genes in glioblastoma multiforme.
Cell Death Dis. 2010; 1:e8 [PubMed] Free Access to Full Article Related Publications
Disruption of apoptosis is considered as an important factor aiding tumorigenesis, and aberrant DNA methylation of apoptosis-associated genes could be an important and significant mechanism through which tumor cells avoid apoptosis. However, little is known about (1) the impact of methylation status of apoptosis-associated genes on the presence of apoptosis evasion phenotype in glioma; and (2) the molecular mechanism governing the aberrant methylation of apoptosis-associated genes in glioma. By analyzing human glioma biopsies, we first show that low level of apoptosis in tumor is correlated with aberrant methylation of the bcl-2, bax and XAF-1 genes, but not with the aberrant methylation of the bcl-w, survivin, TMS1, caspase-8 and HRK genes. Our work also indicates that the expression levels of DNA methyltransferase 1 (Dnmt1), Dnmt3b and Dnmt1/Dnmt3a coregulate the methylation status of survivin, TMS1 and caspase-8, whereas no correlation was observed between the expression level of Dnmts and the methylation status of the bcl-w, bcl-2, bax, XAF-1 and HRK genes. Thus, these results indicate that the epigenetic regulation of some apoptosis-regulated genes could dictate whether glioma harbors the apoptosis evasion phenotype, and provide some bases to the identification of the methylation machineries of apoptosis-associated genes for which the Dnmt expression acts as a limiting factor.

Related: Apoptosis BIRC5

Nakamura M, Shimada K, Konishi N
The role of HRK gene in human cancer.
Oncogene. 2008; 27 Suppl 1:S105-13 [PubMed] Related Publications
Apoptosis regulators play one of the most critical roles in tumorigenesis, and an imbalance between cell proliferation and apoptosis may contribute to tumor progression. HRK was itself originally identified as a proapoptotic gene induced by diminished levels of cytokine in hematopoietic cells and cultured neurons and repressed by the expression of death-repressor proteins. A few analyses of HRK protein expression in primary central nervous system lymphomas have been performed, and little is known about the epigenetic or post-transcriptional mechanisms that may participate in HRK inactivation. Here we show the data on the 5'-CpG methylation status, loss of heterozygosity on 12q13.1 and its association with HRK expression in human malignancies, including prostate cancers, astrocytic tumors and primary central nervous system lymphomas. Aberrant methylation of CpG islands within the promoter is an epigenetic event largely responsible for the silencing of the HRK gene and subsequent low apoptotic counts in our series of malignancies. Inactivation of HRK apparently occurs in a substantial proportion of all tumor phenotypes and, as a potential proapoptotic gene, HRK may contribute to the development and progression of many human cancers.

Related: Apoptosis Brain and Spinal Cord Tumours Chromosome 12 Cancer Prevention and Risk Reduction Prostate Cancer

Gelebart P, Zak Z, Anand M, et al.
Interleukin-21 effectively induces apoptosis in mantle cell lymphoma through a STAT1-dependent mechanism.
Leukemia. 2009; 23(10):1836-46 [PubMed] Related Publications
Interleukin-21 (IL-21) has been recently shown to modulate the growth of specific types of B-cell neoplasm. Here, we studied the biological effects of IL-21 in mantle cell lymphoma (MCL). All MCL cell lines and tumors examined expressed the IL-21 receptor. Addition of recombinant IL-21 (rIL-21) in vitro effectively induced STAT1 activation and apoptosis in MCL cells. As STAT1 is known to have tumor-suppressor functions, we hypothesized that STAT1 is important in mediating IL-21-induced apoptosis in MCL cells. In support of this hypothesis, inhibition of STAT1 expression using siRNA significantly decreased the apoptotic responses induced by IL-21. To further investigate the mechanism of IL-21-mediated apoptosis, we employed oligonucleotide arrays to evaluate changes in the expression of apoptosis-related genes induced by rIL-21; rIL-21 significantly upregulated three proapoptotic proteins (BIK, NIP3 and HARAKIRI) and downregulated two antiapoptotic proteins (BCL-2 and BCL-XL/S) as well as tumor necrosis factor-alpha. Using an ELISA-based assay, we demonstrated that rIL-21 significantly decreased the DNA binding of nuclear factor-kappaB, a transcriptional factor known to be a survival signal for MCL cells. To conclude, IL-21 can effectively induce apoptosis in MCL via a STAT1-dependent pathway. Further understanding of IL-21-mediated apoptosis in MCL may be useful in designing novel therapeutic approaches for this disease.

Related: Apoptosis Mantle Cell Lymphoma

Giefing M, Wierzbicka M, Rydzanicz M, et al.
Chromosomal gains and losses indicate oncogene and tumor suppressor gene candidates in salivary gland tumors.
Neoplasma. 2008; 55(1):55-60 [PubMed] Related Publications
The incidence of salivary gland tumor in Poland is growing in the last two decades. Simultaneously a progress in understanding the genetic mechanisms of formation of this tumor was achieved by detecting several genes like PLAG1 involved in its pathogenesis. In this study we perform a whole genome, CGH analysis with the aim to identify recurrent, chromosomal copy number changes possibly indicating novel tumor suppressor gene or oncogene loci. 29 salivary tumor samples: Cystadenolymphoma-warthin (15) and adenoma polymorphum (14) located in the parotid (27) and submandibular gland (2) were collected and CGH was performed. The established copy number profiles were compared in order to asses the smallest common region of gains and losses. The delineated regions were further analyzed with the UCSC Genome Browser on Human Mar. 2006 Assembly to asses their gene content. Altogether, salivary gland tumors presented a different aberration pattern than these reported for head and neck squamous cell carcinoma (HNSCC) but no significant differences were observed between Warthin and adenoma polymorphum tumors. Moreover, several potential tumor suppressor genes and oncogenes were identified in the smallest, common altered regions. We show a frequent deletion of the harakiri gene (12q24.2) in 12/29 tumors and TP53 gene (17p13.1) in 11/29 tumors as potential tumor suppressors in salivary gland cancers. Besides, we detected a frequent amplification of the 13q22.1-22.2 region in 13/29 cases harboring the KLF5 and KLF12 genes. KLF5 regulates the expression of survivin, an oncogene widely expressed in the majority of human cancers. The observed alterations may indicate important genetic events in the formation of salivary gland tumors. Especially the amplification in 13q may be a mechanism contributing to the expression of survivin and tumor progression.

Related: Salivary Gland Cancer

Higuchi T, Nakamura M, Shimada K, et al.
HRK inactivation associated with promoter methylation and LOH in prostate cancer.
Prostate. 2008; 68(1):105-13 [PubMed] Related Publications
OBJECTIVES: Recent studies in selected human tumors have demonstrated reduced expression of HRK with hypermethylation. Because no similar study has been performed specifically in prostatic lesions, we examined whether the methylation status of HRK is altered in prostate cancers.
METHODS: We chose to analyze the hypermethylation status of HRK, the expression of HRK protein and mRNA with 12q13.1 loss of heterozygosity (LOH) and with p53 mutation, and lesion apoptotic indices as determined by transferase-mediated digoxigenin-tagged 16-desoxy-uridine-triphosphate nick end-labeling (TUNEL) assays in 53 prostate cancers.
RESULTS: Twenty of the 53 prostate cancers (38%) demonstrated hypermethylation in either the promoter or in exon 1 and, more significantly, the loss of HRK expression observed in 14 cancers by immunohistochemistry (IHC) was associated with promoter methylation. In addition, high apoptotic indices in tumors were related to positive HRK expression. Prostate cancers demonstrating HRK methylation also showed methylation of multiple other genes, such as p14(ARF), p16(INK4a), O(6)-MGMT, and GTS-P, but, with the exception of one case, p53 mutations were not detected. When compared to tumors having a Gleason score (GS) of 5-6, a significant difference in the apoptotic indices was found among prostate cancers of GS 7 (P < 0.001) or GS 8-9 (P = 0.007). We also detected a close correlation between the loss of HRK expression and decreased apoptosis in GS 5-6 and GS 7 tumors (P = 0.008, P < 0.001, respectively).
CONCLUSIONS: HRK appears to be inactivated principally by promoter hypermethylation in prostate cancers. We further suggest that the decreased expression of HRK may play an important role in tumor progression by modulating apoptotic cell death.

Related: Apoptosis Prostate Cancer TP53

Nakamura M, Ishida E, Shimada K, et al.
Defective expression of HRK is associated with promoter methylation in primary central nervous system lymphomas.
Oncology. 2006; 70(3):212-21 [PubMed] Related Publications
OBJECTIVES: Recently, it has been reported that expression of the HRK gene was significantly reduced by hypermethylation in astrocytic tumors. Our aim is to verify the alterations in the HRK gene in primary central nervous system lymphomas (PCNSLs).
METHODS: We analyzed the hypermethylation status and expression of the gene and 12q13.1 loss of heterozygosity in 31 PCNSLs.
RESULTS: A total of 13 PCNSLs (31%) demonstrated hypermethylation in either the promoter or exon 1; loss of HRK expression was immunohistochemically observed in 9 tumors and was significantly associated with promoter methylation. In addition, higher apoptotic counts were associated with HRK positivity. PCNSLs with HRK methylation also showed methylation of multiple genes, such as p14ARF, p16INK4a, RB1, p27Kip1 and O6-MGMT. Patients with tumors demonstrating concurrent methylation of more than half of their genes demonstrated significantly poorer survival and earlier recurrence. Hypermethylation of the HRK promoter alone was not associated with overall outcome, but relapse-free survival was significantly shorter.
CONCLUSIONS: Our findings suggest that transcriptional repression of HRK is caused by promoter hypermethylation in PCNSL, and that the loss of HRK associated with the methylation profile of other genes is a potential step in the modulation of cellular death by apoptosis during PCNSL tumorigenesis.

Related: Apoptosis Brain and Spinal Cord Tumours CDKN1B RB1

Holleman A, den Boer ML, de Menezes RX, et al.
The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia.
Blood. 2006; 107(2):769-76 [PubMed] Free Access to Full Article Related Publications
Childhood acute lymphoblastic leukemia (ALL) consists of various subtypes that respond differently to cytotoxic drugs and therefore have a markedly different clinical outcome. We used microarrays to investigate, in 190 children with ALL at initial diagnosis, whether 70 key apoptosis genes were differentially expressed between leukemic subgroups defined by lineage, genetic subtype, in vitro drug resistance, and clinical outcome. The expression of 44 of 70 genes was significantly different in T-versus B-lineage ALL, 22 genes differed in hyperdiploid versus nonhyperdiploid, 16 in TEL-AML1-positive versus-negative, and 13 in E2A-rearranged versus germ-line B-lineage ALL. Expression of MCL1 and DAPK1 was significantly associated with prednisolone sensitivity, whereas BCL2L13, HRK, and TNF were related to L-asparaginase resistance. BCL2L13 overexpression was also associated with unfavorable clinical outcome (P < .001). Multivariate analysis including known risk factors revealed that BCL2L13 expression was an independent prognostic factor (P = .011). The same trend was observed in a validation group of 92 children with ALL treated on a different protocol at St Jude (P = .051). In conclusion, ALL subtypes have a unique expression pattern of apoptosis genes and our data suggest that selective genes are linked to cellular drug resistance and prognosis in childhood B-lineage ALL.

Related: Apoptosis Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology

Nakamura M, Ishida E, Shimada K, et al.
Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas.
Acta Neuropathol. 2005; 110(4):402-10 [PubMed] Related Publications
To detect and identify the genetic alterations and methylation status of the HRK gene in human glioblastomas, we analyzed a cohort of astrocytic tumors for hypermethylation, loss of heterozygosity on 12q13.1, and gene expression. Our study examined a series of 36 diffuse low-grade astrocytomas, 32 anaplastic astrocytomas, 64 primary glioblastomas, and 28 secondary glioblastomas that had evolved from either 24 low-grade diffuse astrocytomas or 4 anaplastic astrocytomas. The region around the HRK transcription start site was methylated in 19% of diffuse astrocytomas, in 22% of anaplastic astrocytomas, in 27% of primary glioblastomas, and in 43% of secondary glioblastomas. HRK expression was significantly reduced in 61% of secondary glioblastomas as compared to other types of tumors, and aberrant methylation was closely associated with loss of expression. Reverse transcription-PCR analysis also demonstrated a clear agreement between reduced HRK protein levels and low or absent HRK transcripts. Lack of HRK immunoreactivity was significantly correlated with a low apoptotic index, whereas a strong association between methylation status and apoptosis was found only in secondary glioblastomas. Abnormal methylation of HRK was detected in astrocytic tumors concurrent with methylation of multiple genes, including p16(INK4a) and p14(ARF). Interestingly, these epigenetic changes in secondary glioblastoma were further associated with wild-type p53. Our findings suggest that HRK is inactivated mainly by aberrant DNA methylation in astrocytic tumors and that reduced HRK expression contributes to the loss of apoptotic control in high-grade tumors. Reduced expression of HRK may serve as one important molecular mechanism in progression to secondary glioblastoma.

Related: Apoptosis Chromosome 22

Guo Y, Niiya H, Azuma T, et al.
Direct recognition and lysis of leukemia cells by WT1-specific CD4+ T lymphocytes in an HLA class II-restricted manner.
Blood. 2005; 106(4):1415-8 [PubMed] Related Publications
Wilms tumor gene 1 product (WT1) has been recognized as an attractive target antigen of immunotherapy for various malignancies including leukemia. Because tumor-associated antigen-specific CD4+ T lymphocytes undoubtedly play an important role in the induction of an antitumor immune response, we attempted to generate WT1-specific CD4+ T lymphocytes in vitro and examined their antileukemia functions. A CD4+ T-cell line, designated NIK-1, which proliferated and produced Th1 cytokines specifically in response to stimulation with the WT1-derived peptide, WT1(337-347) LSHLQMHSRKH, in an HLA-DP5-restricted manner was established. NIK-1 exhibited cytotoxicity against HLA-DP5-positive, WT1-expressing leukemia cells but did not lyse HLA-DP5-negative, WT1-expressing leukemia cells or HLA-DP5-positive, WT1-negative cells. NIK-1 did not inhibit colony formation by normal bone marrow cells of HLA-DP5-positive individuals. This is the first report to describe WT1-specific and HLA class II-restricted CD4+ T lymphocytes possessing direct cytotoxic activity against leukemia cells.

Related: Leukemia WT1

Mao X, Orchard G, Lillington DM, et al.
BCL2 and JUNB abnormalities in primary cutaneous lymphomas.
Br J Dermatol. 2004; 151(3):546-56 [PubMed] Related Publications
BACKGROUND: BCL2 is upregulated in nodal and extranodal B-cell non-Hodgkin's lymphomas, with a consequent antiapoptotic effect. However, loss of BCL2 has also been noted in some malignancies, suggesting a different molecular pathogenesis.
OBJECTIVES: To investigate genomic and protein expression status of BCL2 and to compare the results with that of JUNB in primary cutaneous lymphomas (PCLs).
METHODS: We analysed gene copy number of BCL2 and JUNB in 88 DNA samples from 80 patients with PCL consisting of Sézary syndrome/mycosis fungoides (SS/MF), primary cutaneous B-cell lymphoma (PCBCL) and primary cutaneous CD30+ anaplastic large cell lymphoma (C-ALCL) by the use of real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC). Real-time PCR and IHC findings were subsequently compared with the results of additional fluorescent in situ hybridization (FISH) analysis of 23 cases of SS and Affymetrix cDNA expression microarray study of two primary cutaneous T-cell lymphoma (CTCL) cell lines.
RESULTS: Real-time PCR analysis showed loss of BCL2 gene copy number in 22 of 80 PCL cases (28%), including 17 of 42 SS/MF, three of 13 C-ALCL and two of 33 PCBCL samples, and gain of BCL2 in four PCBCL samples. Gain of JUNB was identified in 18 of 71 PCL cases (25%), including nine of 35 SS/MF, seven of 13 C-ALCL and two of 31 PCBCL samples. IHC analysis revealed absent nuclear expression of BCL2 protein in 47 of 73 PCL cases, comprising 28 of 36 SS/MF, eight of eight C-ALCL and 11 of 29 PCBCL cases. In contrast, BCL2 protein expression was detected in 26 of 73 PCL cases, consisting of 18 of 29 PCBCL and eight of 36 SS/MF cases. JUNB protein expression was present in tumour cells from 30 of 33 of SS/MF and eight of eight C-ALCL, and was absent in tumour cells from 18 of 27 PCBCL cases. A comparison between BCL2 and JUNB revealed loss of BCL2 and gain of JUNB in five of 35 SS/MF samples, and expression of JUNB protein and absent BCL2 expression in 25 SS/MF and eight of eight C-ALCL cases. In contrast, expression of BCL2 and absent JUNB expression were detected in 67% of PCBCL cases. Additional FISH analysis revealed deletion of BCL2 in 19 of 23 SS cases (83%), including eight cases with BCL2 loss shown by real-time PCR. Furthermore, Affymetrix expression microarray demonstrated decreased expression of proapoptotic and antiapoptotic genes involved in BCL2 signalling pathways such as BOK, BIM, HRK, RASA1 and STAT2 in two CTCL cell lines with BCL2 loss and absent BCL2 expression. Increased expression of JUNB was also identified in the MF cell line.
CONCLUSIONS: These findings provide a comprehensive assessment of BCL2 and JUNB status in PCL, and suggest that there is a selection pressure in a subset of CTCL cases for tumour cells showing BCL2 loss and upregulation of JUNB primarily through chromosomal deletion and amplification, respectively.

Related: BCL2 gene FISH Skin Cancer

Obata T, Toyota M, Satoh A, et al.
Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer.
Clin Cancer Res. 2003; 9(17):6410-8 [PubMed] Related Publications
PURPOSE: Aberrant methylation of CpG islands can be a good molecular marker for identifying genes inactivated in cancer. We found the proapoptotic gene HRK to be a target for hypermethylation in human cancers and examined the role of such methylation in silencing the gene's expression.
EXPERIMENTAL DESIGN: Methylation of HRK was evaluated by bisulfite-PCR and bisulfite sequencing in a group of colorectal and gastric cancer cell lines and primary cancers. Gene expression and histone acetylation were examined by reverse transcription-PCR and chromatin immunoprecipitation analyses, respectively. Apoptosis of cancer cells after treatment with a DNA methyltransferase inhibitor and/or histone deacetylase inhibitor was examined with fluorescence-activated cell-sorting analysis.
RESULTS: The region around the HRK transcription start site was methylated in 36% of colorectal and 32% of gastric cancer cell lines and was closely associated with loss of expression in those cell types. HRK expression was restored by treatment with a methyltransferase inhibitor, 5-aza-deoxycytidine, and enhanced further by addition of histone deacetylase inhibitor trichostatin A or depsipeptide. Such restoration of HRK expression was well correlated with induction of apoptosis and enhancement of Adriamycin-induced apoptosis. Expression of other proapoptotic genes, including BAX, BAD, BID, and PUMA, was unaffected by treatment with 5-aza-deoxycytidine. Aberrant methylation of HRK was also frequently detected in primary colorectal cancers that showed methylation of multiple genes, including p16INK4A and hMLH1, and was associated with wild-type p53.
CONCLUSION: HRK methylation can be a useful molecular target for cancer therapy in a subset of colorectal and gastric cancers.

Related: Apoptosis Azacitidine Colorectal (Bowel) Cancer Doxorubicin Stomach Cancer Gastric Cancer

Ogi K, Toyota M, Ohe-Toyota M, et al.
Aberrant methylation of multiple genes and clinicopathological features in oral squamous cell carcinoma.
Clin Cancer Res. 2002; 8(10):3164-71 [PubMed] Related Publications
The purpose of this study was to examine the methylation profile of various oral squamous cell carcinomas and to correlate the methylation of particular chromosomal loci with the clinicopathological features of the tumors. A semiquantitative analysis of the methylation status of 12 loci in 96 primary tumors and 13 cell lines was carried out. Methylation frequency was calculated as the percentage of methylated alleles detected by bisulfate-PCR. Of the 12 loci examined, 9 (p16INK4A, p15INK4B, p14ARF, DCC, DAP kinase, MINT1, MINT2, MINT27, and MINT31) exhibited aberrant methylation at various frequencies, whereas 3 (hMLH1, HRK, and CACNA1G) showed no methylation. Dense methylation of the 5' CpG island of DAP kinase and MINT1 was well correlated with loss of gene expression. In addition, methylation of DCC was correlated with bone invasion by gingival tumors (P = 0.036), with aggressive invasiveness of tumors of the tongue (P = 0.046), and with reduced survival (P = 0.050). Methylation of MINT1 and MINT31 also correlated with poor prognoses (P = 0.058 and 0.041), whereas methylation of p14ARF correlated with a good prognosis (P = 0.021). Cox regression analysis showed methylation of MINT31 to be an independent predictor of outcome (hazard ratio, 3.79; 95% confidence interval, 1.58-9.10) and to be associated with the T4 disease group (hazard ratio, 5.71; 95% confidence interval, 1.25-26.07). Analysis of DNA methylation is a useful approach to evaluation of the biological characteristics of oral cancers and may be a useful diagnostic indicator of patient prognosis.

Related: Oral Cancer

Sanz C, Horita M, Fernandez-Luna JL
Fas signaling and blockade of Bcr-Abl kinase induce apoptotic Hrk protein via DREAM inhibition in human leukemia cells.
Haematologica. 2002; 87(9):903-7 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: The apoptotic Bcl-2 family member Hrk is transcriptionally silenced via DREAM in hematopoietic progenitor cell lines, and is specifically induced after growth factor withdrawal. Given that expression of Hrk is sufficient to induce apoptosis, we studied the expression of this apoptotic protein and its regulatory mechanism in human leukemia cells.
DESIGN AND METHODS: K562 chronic myeloid leukemia cells were treated with STI571, a Bcr-Abl kinase inhibitor, and the Jurkat T-cell leukemia cell line was incubated with agonistic anti-Fas antibodies. Following treatment, we correlated the expression of Hrk protein with the DNA binding capacity of DREAM, and the induction of apoptosis.
RESULTS: We show that treatment of K562 with STI571 blocks the binding of DREAM to the Hrk gene and allows the expression of Hrk, which correlates with the induction of apoptosis. Similarly, treatment of Jurkat cells with agonistic anti-Fas antibodies triggers the expression of Hrk through DREAM inactivation. Interestingly, inhibition of caspases, by culturing Jurkat cells in the presence of z-VAD-fmk, abrogates Fas-mediated hrk expression and apoptosis. Furthermore, in vitro analysis shows that active recombinant caspase-3 releases a fragment from the DREAM protein, suggesting that caspase-3 may be upstream of DREAM.
INTERPRETATION AND CONCLUSIONS: These data suggest that apoptosis inducers as diverse as oncoprotein inhibitors and cell death receptor activators trigger Hrk expression via blockade of DREAM in leukemia cells, and this apoptotic pathway may be regulated, at least in some systems, by the proteolytic activity of caspase-3.

Related: TNFRSF6 gene Apoptosis CASP3 Leukemia Signal Transduction

Ory K, Lebeau J, Levalois C, et al.
Apoptosis inhibition mediated by medroxyprogesterone acetate treatment of breast cancer cell lines.
Breast Cancer Res Treat. 2001; 68(3):187-98 [PubMed] Related Publications
Several reports suggested that steroidogenic hormones could be directly involved in the regulation of apoptosis in vitro, but whether this is due to blocking or promoting mechanism of these hormones remains controversial. However, it was shown that progesterone exhibited a protective effect against the apoptotic process during mouse mammary gland involution in vivo. In this study, we analyzed the effect of medroxyprogesterone acetate (MPA) treatment, an agonist of progesterone, on serum starvation induced apoptosis on breast cancer cell lines. Positive and negative progesterone receptor (PgR+ and PgR-) breast cancer cell lines were treated with MPA (10 nM), either in standard culture conditions or in serum-free medium to induce apoptosis. Cell survival, proliferation and apoptosis were simultaneously analyzed with the expression of apoptosis-related genes measured by a real time quantitative RT-PCR. At non cytotoxic doses, MPA protected PgR+ T47-D, MCF-7 and H466-B cell lines against serum depletion-induced apoptosis, while MPA did not protect PgR-MDA-MB-231 cells against serum depletion induced apoptosis. In PgR+ cell lines and in concordance with the protective effect, the pro-apoptotic HRK and BAK1 mRNAs were up-regulated after apoptosis induction, while they were no more induced in condition of protection against apoptosis after MPA treatment. We also observed, specifically in PgR+ cells, an up-regulation of BCLX-L and BCLX-S and a down-regulation of BCL2 mRNAs, which are specific to the MPA response and unrelated to apoptotic process. Involvement of these genes with regard to the MPA-mediated protection against apoptosis is discussed.

Related: Apoptosis Breast Cancer BCL2 gene


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