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PAWR; PRKC, apoptosis, WT1, regulator (12q21)

Gene Summary

Gene:PAWR; PRKC, apoptosis, WT1, regulator
Aliases: PAR4, Par-4
Location:12q21
Summary:The tumor suppressor WT1 represses and activates transcription. The protein encoded by this gene is a WT1-interacting protein that itself functions as a transcriptional repressor. It contains a putative leucine zipper domain which interacts with the zinc finger DNA binding domain of WT1. This protein is specifically upregulated during apoptosis of prostate cells. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:PRKC apoptosis WT1 regulator protein
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (21)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 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.

  • Chromosome 12
  • Genotype
  • Synaptotagmin I
  • Single Nucleotide Polymorphism
  • Promoter Regions
  • European Continental Ancestry Group
  • HNF1B
  • Gene Expression Profiling
  • Melanocytes
  • Transfection
  • BID
  • Gene Silencing
  • Cancer Gene Expression Regulation
  • Genomic Instability
  • Cell Proliferation
  • Oligonucleotide Array Sequence Analysis
  • Fatal Outcome
  • Leukemic Gene Expression Regulation
  • Apoptosis Regulatory Proteins
  • Insulin-Like Growth Factor Binding Protein 1
  • PAWR
  • Receptors, Mitogen
  • Skin Cancer
  • Prostate Cancer
  • Tumor Markers
  • Liposarcoma
  • Apoptosis
  • Neoplastic Cell Transformation
  • Disease Progression
  • African Americans
  • Acute Myeloid Leukaemia
  • Base Sequence
  • Epigenetics
  • Breast Cancer
  • MCF-7 Cells
  • Gene Expression
  • Antibiotics, Antineoplastic
  • Homeodomain Proteins
  • Genome-Wide Association Study
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Prostate CancerPAWR and Prostate Cancer View Publications2
Breast CancerPAWR and Breast Cancer View Publications2
Acute Myeloid Leukaemia (AML)PAWR and Acute Myeloid Leukaemia View Publications1
Skin CancerPAWR and Skin Cancer View Publications1

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: PAWR (cancer-related)

Walsh CA, Bolger JC, Byrne C, et al.
Global gene repression by the steroid receptor coactivator SRC-1 promotes oncogenesis.
Cancer Res. 2014; 74(9):2533-44 [PubMed] Related Publications
Transcriptional control is the major determinant of cell fate. The steroid receptor coactivator (SRC)-1 enhances the activity of the estrogen receptor in breast cancer cells, where it confers cell survival benefits. Here, we report that a global analysis of SRC-1 target genes suggested that SRC-1 also mediates transcriptional repression in breast cancer cells. Combined SRC-1 and HOXC11 ChIPseq analysis identified the differentiation marker, CD24, and the apoptotic protein, PAWR, as direct SRC-1/HOXC11 suppression targets. Reduced expression of both CD24 and PAWR was associated with disease progression in patients with breast cancer, and their expression was suppressed in metastatic tissues. Investigations in endocrine-resistant breast cancer cell lines and SRC-1(-/-)/PyMT mice confirmed a role for SRC-1 and HOXC11 in downregulation of CD24 and PAWR. Through bioinformatic analysis and liquid chromatography/mass spectrometry, we identified AP1 proteins and Jumonji domain containing 2C (JMD2C/KDM4C), respectively, as members of the SRC-1 interactome responsible for transcriptional repression. Our findings deepen the understanding of how SRC-1 controls transcription in breast cancers.

Related: Breast Cancer HOXC11 gene


Jagtap JC, Dawood P, Shah RD, et al.
Expression and regulation of prostate apoptosis response-4 (Par-4) in human glioma stem cells in drug-induced apoptosis.
PLoS One. 2014; 9(2):e88505 [PubMed] Free Access to Full Article Related Publications
Gliomas are the most common and aggressive of brain tumors in adults. Cancer stem cells (CSC) contribute to chemoresistance in many solid tumors including gliomas. The function of prostate apoptosis response-4 (Par-4) as a pro-apoptotic protein is well documented in many cancers; however, its role in CSC remains obscure. In this study, we aimed to explore the role of Par-4 in drug-induced cytotoxicity using human glioma stem cell line--HNGC-2 and primary culture (G1) derived from high grade glioma. We show that among the panel of drugs- lomustine, carmustine, UCN-01, oxaliplatin, temozolomide and tamoxifen (TAM) screened, only TAM induced cell death and up-regulated Par-4 levels significantly. TAM-induced apoptosis was confirmed by PARP cleavage, Annexin V and propidium iodide staining and caspase-3 activity. Knock down of Par-4 by siRNA inhibited cell death by TAM, suggesting the role of Par-4 in induction of apoptosis. We also demonstrate that the mechanism involves break down of mitochondrial membrane potential, down regulation of Bcl-2 and reduced activation of Akt and ERK 42/44. Secretory Par-4 and GRP-78 were significantly expressed in HNGC-2 cells on exposure to TAM and specific antibodies to these molecules inhibited cell death suggesting that extrinsic Par-4 is important in TAM-induced apoptosis. Interestingly, TAM decreased the expression of neural stem cell markers--Nestin, Bmi1, Vimentin, Sox2, and Musashi in HNGC-2 cell line and G1 cells implicating its potential as a stemness inhibiting drug. Based on these data and our findings that enhanced levels of Par-4 sensitize the resistant glioma stem cells to drug-induced apoptosis, we propose that Par-4 may be explored for evaluating anti-tumor agents in CSC.

Related: Apoptosis CASP3


Egan JB, Barrett MT, Champion MD, et al.
Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements.
PLoS One. 2014; 9(2):e87113 [PubMed] Free Access to Full Article Related Publications
Liposarcoma is the most common soft tissue sarcoma, but little is known about the genomic basis of this disease. Given the low cell content of this tumor type, we utilized flow cytometry to isolate the diploid normal and aneuploid tumor populations from a well-differentiated liposarcoma prior to array comparative genomic hybridization and whole genome sequencing. This work revealed massive highly focal amplifications throughout the aneuploid tumor genome including MDM2, a gene that has previously been found to be amplified in well-differentiated liposarcoma. Structural analysis revealed massive rearrangement of chromosome 12 and 11 gene fusions, some of which may be part of double minute chromosomes commonly present in well-differentiated liposarcoma. We identified a hotspot of genomic instability localized to a region of chromosome 12 that includes a highly conserved, putative L1 retrotransposon element, LOC100507498 which resides within a gene cluster (NAV3, SYT1, PAWR) where 6 of the 11 fusion events occurred. Interestingly, a potential gene fusion was also identified in amplified DDR2, which is a potential therapeutic target of kinase inhibitors such as dastinib, that are not routinely used in the treatment of patients with liposarcoma. Furthermore, 7 somatic, damaging single nucleotide variants have also been identified, including D125N in the PTPRQ protein. In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.

Related: Chromosome 11 Chromosome 12


Chaudhry P, Fabi F, Singh M, et al.
Prostate apoptosis response-4 mediates TGF-β-induced epithelial-to-mesenchymal transition.
Cell Death Dis. 2014; 5:e1044 [PubMed] Free Access to Full Article Related Publications
A growing body of evidence supports that the epithelial-to-mesenchymal transition (EMT), which occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Transforming growth factor-β (TGF-β) is known to induce EMT in a number of cancer cell types; however, the mechanism underlying this transition process is not fully understood. In this study we have demonstrated that TGF-β upregulates the expression of tumor suppressor protein Par-4 (prostate apoptosis response-4) concomitant with the induction of EMT. Mechanistic investigations revealed that exogenous treatment with each TGF-β isoform upregulates Par-4 mRNA and protein levels in parallel levels of phosphorylated Smad2 and IκB-α increase. Disruption of TGF-β signaling by using ALK5 inhibitor, neutralizing TGF-β antibody or phosphoinositide 3-kinase inhibitor reduces endogenous Par-4 levels, suggesting that both Smad and NF-κB pathways are involved in TGF-β-mediated Par-4 upregulation. NF-κB-binding sites in Par-4 promoter have previously been reported; however, using chromatin immunoprecipitation assay we showed that Par-4 promoter region also contains Smad4-binding site. Furthermore, TGF-β promotes nuclear localization of Par-4. Prolonged TGF-β3 treatment disrupts epithelial cell morphology, promotes cell motility and induces upregulation of Snail, vimentin, zinc-finger E-box binding homeobox 1 and N-Cadherin and downregulation of Claudin-1 and E-Cadherin. Forced expression of Par-4, results in the upregulation of vimentin and Snail expression together with increase in cell migration. In contrast, small interfering RNA-mediated silencing of Par-4 expression results in decrease of vimentin and Snail expression and prevents TGF-β-induced EMT. We have also uncovered a role of X-linked inhibitor of apoptosis protein in the regulation of endogenous Par-4 levels through inhibition of caspase-mediated cleavage. In conclusion, our findings suggest that Par-4 is a novel and essential downstream target of TGF-β signaling and acts as an important factor during TGF-β-induced EMT.

Related: Endometrial (Uterus) Cancer Endometrial Cancer Signal Transduction MADH4 Cervical Cancer


Partanen JI, Tervonen TA, Klefström J
Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4.
Philos Trans R Soc Lond B Biol Sci. 2013; 368(1629):20130111 [PubMed] Free Access to Full Article Related Publications
The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine-threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz-Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer?

Related: Cancer Prevention and Risk Reduction


Lu C, Li JY, Ge Z, et al.
Par-4/THAP1 complex and Notch3 competitively regulated pre-mRNA splicing of CCAR1 and affected inversely the survival of T-cell acute lymphoblastic leukemia cells.
Oncogene. 2013; 32(50):5602-13 [PubMed] Free Access to Full Article Related Publications
Although the intensification of therapy for children with T-cell acute lymphoblastic leukemia (T-ALL) has substantially improved clinical outcomes, T-ALL remains an important challenge in pediatric oncology. Here, we report that the cooperative synergy between prostate apoptosis response factor-4 (Par-4) and THAP1 induces cell cycle and apoptosis regulator 1 (CCAR1) gene expression and cellular apoptosis in human T-ALL cell line Jurkat cells, CEM cells and primary cultured neoplastic T lymphocytes from children with T-ALL. Par-4 and THAP1 collaborated to activate the promoter of CCAR1 gene. Mechanistic investigations revealed that Par-4 and THAP1 formed a protein complex by the interaction of their carboxyl termini, and THAP1 bound to CCAR1 promoter though its zinc-dependent DNA-binding domain at amino terminus. Par-4/THAP1 complex and Notch3 competitively bound to CCAR1 promoter and competitively modulated alternative pre-mRNA splicing of CCAR1, which resulted in two different transcripts and played an opposite role in T-ALL cell survival. Despite Notch3 induced a shift splicing from the full-length isoform toward a shorter form of CCAR1 mRNA by splicing factor SRp40 and SRp55, Par-4/THAP1 complex strongly antagonized this inductive effect. Our finding revealed a mechanistic rationale for Par-4/THAP1-induced apoptosis in T-ALL cells that would be of benefit to develop a new therapy strategy for T-ALL.

Related: Apoptosis NOTCH3


Jiang P, Yu GY, Zhang Y, et al.
Down-regulation of protease-activated receptor 4 in lung adenocarcinoma is associated with a more aggressive phenotype.
Asian Pac J Cancer Prev. 2013; 14(6):3793-8 [PubMed] Related Publications
The role of protease-activated receptors (PARs) in lung tumors is controversial. Although PAR4 is preferentially expressed in human lung tissues, its possible significance in lung cancer has not been defined. The studies reported herein used a combination of clinical observations and molecular methods. Surgically resected lung adenocarcinomas and associated adjacent normal lung tissues were collected and BEAS-2B and NCI-H157 cell lines were grown in tissue culture. PAR4 expression was evaluated by RT-PCR, RT-qPCR, Western blotting and immunohistochemistry analysis. The results showed that PAR4 mRNA expression was generally decreased in lung adenocarcinoma tissues as compared with matched noncancerous tissues (67.7%) and was associated with poor differentiation (p=0.017) and metastasis (p=0.04). Western blotting and immunohistochemical analysis also showed that PAR4 protein levels were mostly decreased in lung adenocarcinoma tissues (61.3%), and were also associated with poor differentiation (p=0.035) and clinical stage (p=0.027). Moreover, PAR4 expression was decreased in NCI-H157 cells as compared with BEAS-2B cells. In conclusion, PAR4 expression is significantly decreased in lung adenocarcinoma, and down-regulation of PAR4 is associated with a more clinically aggressive phenotype. PAR4 may acts as a tumor suppressor in lung adenocarcinoma.

Related: Lung Cancer


Coutinho-Camillo CM, Lourenço SV, Nonogaki S, et al.
Expression of PAR-4 and PHLDA1 is prognostic for overall and disease-free survival in oral squamous cell carcinomas.
Virchows Arch. 2013; 463(1):31-9 [PubMed] Related Publications
PAR-4 is a tumor suppressor protein with a pro-apoptotic function and down-regulation of PAR-4 is seen in a variety of tumors. PHLDA1 gene overexpression has been shown to reduce cell proliferation and induce cell death in a variety of cell types. In this study, 229 cases of oral squamous cell carcinoma (OSCC), arranged in a tissue microarray, were analyzed by immunohistochemistry. PAR-4 expression was predominantly moderate to strong and expression of PHLDA1 was predominantly negative or weak. Cytoplasmic expression of PAR-4 was associated with advanced clinical stage. Expression of PHLDA1 was associated with advanced clinical stage of the tumour. Five-year overall and disease-free survival rates differed significantly between cases that did and cases that did not express PHLDA1, and by multivariate analysis, expression of PHLDA1 and PAR-4 were independent prognostic factors in OSCC patients. Expression of PAR-4 and PHLDA1 is altered in OSCC and might be a valuable prognostic indicator for this disease.

Related: Oral Cancer


Hu YL, Zhong D, Pang F, et al.
HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes.
Genet Mol Res. 2013; 12(2):1327-35 [PubMed] Related Publications
Prostate cancer is one of the most commonly diagnosed male malignancies. Genome wide association studies have revealed HNF1b to be a major risk gene for prostate cancer susceptibility. We examined the mechanisms of involvement of HNF1b in prostate cancer development. We integrated data from Gene Expression Omnibus prostate cancer genes from the Dragon Database of Genes Implicated in Prostate Cancer, and used meta-analysis data to generate a panel of HNF1b-associated prostate cancer risk genes. An RT-PCR was used to assess expression levels in DU145, PC3, LNCaP, and RWEP-1 cells. Twelve genes (BAG1, DDR1, ERBB4, ESR1, HSPD1, IGFBP2, IGFBP5, NR4A1, PAWR, PIK3CG, RAP2A, and TPD52) were found to be associated with both HNF1b and prostate cancer risk. Six of them (BAG1, ERBB4, ESR1, HSPD1, NR4A1, and PIK3CG) were mapped to the KEGG pathway, and submitted to further gene expression assessment. HNF1b, NR4A1, and HSPD1 were found to be highly expressed in the LNCaP androgenic hormone-dependent cell line. Compared to expression levels in wild-type prostate cancer cells, NR4A1, HSPD1, ERBB4, and ESR1 expression levels were also found to be significantly increased in the HNF1b-transfected cells. We conclude that the mechanism of action of HNF1b in prostate cancer involves modulation of the association between androgenic hormone and prostate cancer cells. Gene-gene interaction and coordination should be taken into account to determine relationships between specific loci and diseases.

Related: Prostate Cancer Signal Transduction HNF1B


Yang K, Shen J, Xie YQ, et al.
Promoter-targeted double-stranded small RNAs activate PAWR gene expression in human cancer cells.
Int J Biochem Cell Biol. 2013; 45(7):1338-46 [PubMed] Related Publications
RNA activation is a promising discovery that promoter-targeted double-stranded small RNAs, termed small activating RNAs (saRNAs), can induce gene expression, which represents a novel approach to gene over-expression without traditional vector-based systems. PAWR is a tumor suppressing gene essential for apoptosis and a cancer-selective target for cancer therapeutics. Here our study identified synthetic saRNAs that could activate the expression of PAWR in human cancer cells. Functional analysis of PAWR induction revealed that saRNA treatment induced growth inhibition and apoptosis of cancer cells, and predictably modulated the expression of known downstream target gene Bcl-2. New functional saRNAs can also be harvested by one or two-base shifting of the original target sites. Chromatin immunoprecipitation assays indicated that activation of PAWR is accompanied by reduced dimethylation at histone H3K9 and increased dimethylation at histone H3K4. Moreover, the existence of transcripts in PAWR promoter was detected but its relationship with RNA activation needs more lucubration. These data have enlarged the gene pool of RNAa and hold great promise as an alternative for PAWR-targeted therapeutics.

Related: Apoptosis Cancer Prevention and Risk Reduction


Rah B, Amin H, Yousuf K, et al.
A novel MMP-2 inhibitor 3-azidowithaferin A (3-azidoWA) abrogates cancer cell invasion and angiogenesis by modulating extracellular Par-4.
PLoS One. 2012; 7(9):e44039 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Withaferin A, which is a naturally derived steroidal lactone, has been found to prevent angiogenesis and metastasis in diverse tumor models. It has also been recognized by different groups for prominent anti-carcinogenic roles. However, in spite of these studies on withanolides, their detailed anti-metastatic mechanism of action remained unknown. The current study has poised to address the machinery involved in invasion regulation by stable derivative of Withaferin A, 3-azido Withaferin A (3-azidoWA) in human cervical HeLa and prostate PC-3 cells.
METHODS AND PRINCIPAL FINDINGS: Sub-toxic concentration of 3-azidowithaferin A (3-azido WA) inhibited cancer cell motility and invasion in wound healing and Boyden chamber invasion by suppressing MMP-2 activity in gelatin zymography and its expression has proved to be a major obstacle in chemo-sensitivity. We have uncovered a novel mechanism of 3-azidoWA induced extracellular pro-apoptotic candidate tumor suppressor Par-4 protein stimulation in conditioned media and also noticed a concomitant marked reduction in pAkt and pERK signaling by immunoblot analysis. Furthermore, our zymography results suggest 3-azidoWA induced MMP-2 inhibition was mediated through secretory Par-4. The inhibition of apoptosis by 3-azidoWA could not restore MMP-2 gelatinase activity. In addition to this, our in vivo animal experiments data showed 3-azidoWA abrogated neovascularisation in dose dependent manner in mouse Matrigel plug assay.
CONCLUSION/SIGNIFICANCE: For this report, we found that 3-azidoWA suppressed motility and invasion of HeLa and PC-3 cells in MMP-2 dependent manner. Our in vitro result strongly suggests that sub-toxic doses of 3-azidoWA enhanced the secretion of extracellular Par-4 that abolished secretory MMP-2 expression and activity. Depletion of secretory Par-4 restored MMP-2 expression and invasion capability of HeLa and PC-3 cells. Further, our findings implied that 3-azidoWA attenuated internal phospho-ERK and phospho-Akt expression in a dose dependent manner might play a key role in inhibition of mouse angiogenesis by 3-azidoWA.

Related: Apoptosis MMP2 Angiogenesis and Cancer AKT1 Signal Transduction


Hebbar N, Wang C, Rangnekar VM
Mechanisms of apoptosis by the tumor suppressor Par-4.
J Cell Physiol. 2012; 227(12):3715-21 [PubMed] Free Access to Full Article Related Publications
Par-4 is a pro-apoptotic, tumor suppressor protein that induces apoptosis selectively in cancer cells. Endoplasmic reticulum-stress and higher levels of protein kinase A in tumor cells confer the coveted feature of cancer selective response to extracellular and intracellular Par-4, respectively. Recent studies have shown that systemic Par-4 confers resistance to tumor growth in mice, and that tumor-resistance is transferable by bone-marrow transplantation. Moreover, recombinant Par-4 inhibits the growth of tumors in mice. As systemic Par-4 induces apoptosis via cell surface GRP78, strategies that promote GRP78 trafficking to the cell surface are expected sensitize cancer cells to circulating levels of Par-4. This review illustrates the domains and mechanisms by which Par-4 orchestrates the apoptotic process in both cell culture models and in physiological settings.

Related: Apoptosis Cancer Prevention and Risk Reduction


Egan K, Crowley D, Smyth P, et al.
Platelet adhesion and degranulation induce pro-survival and pro-angiogenic signalling in ovarian cancer cells.
PLoS One. 2011; 6(10):e26125 [PubMed] Free Access to Full Article Related Publications
Thrombosis is common in ovarian cancer. However, the interaction of platelets with ovarian cancer cells has not been critically examined. To address this, we investigated platelet interactions in a range of ovarian cancer cell lines with different metastatic potentials [HIO-80, 59M, SK-OV-3, A2780, A2780cis]. Platelets adhered to ovarian cancer cells with the most significant adhesion to the 59M cell line. Ovarian cancer cells induced platelet activation [P-selectin expression] in a dose dependent manner, with the most significant activation seen in response to the 59M cell line. The platelet antagonists [cangrelor, MRS2179, and apyrase] inhibited 59M cell induced activation suggesting a P2Y12 and P2Y1 receptor mediated mechanism of platelet activation dependent on the release of ADP by 59M cells. A2780 and 59M cells potentiated PAR-1, PAR-4, and TxA2 receptor mediated platelet activation, but had no effect on ADP, epinephrine, or collagen induced activation. Analysis of gene expression changes in ovarian cancer cells following treatment with washed platelets or platelet releasate showed a subtle but valid upregulation of anti-apoptotic, anti-autophagy pro-angiogenic, pro-cell cycle and metabolic genes. Thus, ovarian cancer cells with different metastatic potential adhere and activate platelets differentially while both platelets and platelet releasate mediate pro-survival and pro-angiogenic signals in ovarian cancer cells.

Related: Angiogenesis and Cancer Ovarian Cancer Signal Transduction


Kline CL, Irby RB
The pro-apoptotic protein Prostate Apoptosis Response Protein-4 (Par-4) can be activated in colon cancer cells by treatment with Src inhibitor and 5-FU.
Apoptosis. 2011; 16(12):1285-94 [PubMed] Related Publications
The overexpression of the pro-apoptotic protein Prostate Apoptosis Response Protein-4 in colon cancer has been shown to increase response to the chemotherapeutic agent 5-fluorouracil (5-FU). Although colon cancer cells endogenously express Par-4, the presence or overexpression of Par-4 alone does not cause apoptosis. We hypothesize that Par-4 is inactivated in colon cancer. In colon cancer, the levels and the kinase activity of the nonreceptor tyrosine kinase c-Src increase with tumor progression. One of the downstream effectors of c-Src is Akt1. Akt1 has been shown to inhibit the pro-apoptotic activity of Par-4 in prostate cancer cells. We therefore investigated the potential of activating Par-4 by inhibiting c-Src. Colon carcinoma cell lines were treated with the Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2) in combination with the chemotherapeutic agent 5-FU. Treating cells with PP2 and 5-FU resulted in reduced interaction of Par-4 with Akt1 and with the scaffolding protein 14-3-3σ, and mobilization of Par-4 to the nucleus. Par-4 was shown to interact not only with Akt1 and 14-3-3σ, but also with c-Src. Overexpression of c-Src induced the phosphorylation of Par-4 at tyrosine site/s. Thus, in this study, we have shown that Par-4 can be activated by inhibiting Src with a pharmacological inhibitor and adding a chemotherapeutic agent. The activation of the pro-apoptotic protein Par-4 as reported in this study is a novel mechanism by which apoptosis occurs with a Src kinase inhibitor and 5-FU. In addition, we have demonstrated that the pro-apoptotic activity of endogenously expressed Par-4 can be increased in colon cancer cells.

Related: Apoptosis Fluorouracil AKT1


Naldini A, Morena E, Belotti D, et al.
Identification of thrombin-like activity in ovarian cancer associated ascites and modulation of multiple cytokine networks.
Thromb Haemost. 2011; 106(4):705-11 [PubMed] Related Publications
Blood coagulation cascades can be activated by different mechanisms and to different levels in cancer patients. In a study conducted on the transcriptional profile of epithelial ovarian cancer patients a number of possible links between coagulation and inflammation have been suggested and we and others have reported that, in addition to its central role in blood coagulation and haemostasis, thrombin is a powerful regulator of inflammatory responses. Here, we report that thrombin- like activities were present in the malignant ascites of patients with ovarian carcinoma. Malignant ascites significantly enhanced the release of cytokines/chemokines, which have been previously shown to support tumour progression, such as interleukin (IL)-6, IL-1β, CCL2 and CXCL8, in human peripheral blood mononuclear cells of healthy volunteers. Interestingly, ascites enhanced the release of the anti-inflammatory cytokine IL-10 and inhibited the production of interferon-γ and IL-12. The presence of the anticoagulant antithrombin reversed IL-12 inhibition induced by ascites in human monocytes. Finally, the use of thrombin and of the specific thrombin receptor (PAR) agonist peptides, TFLLRN and AYGPK, suggests that IL-12 inhibition is thrombin-specific and related to PAR-1, but not to PAR-4. These findings underline the tight relationship between the coagulation pathway, where thrombin is the key enzyme, and cytokine modulation, including IL-12 inhibition, which is a critical feature of the tumour microenvironment, and may represent a powerful strategy used by tumours to escape immune surveillance.

Related: Cytokines Ovarian Cancer


Sebbagh M, Olschwang S, Santoni MJ, Borg JP
The LKB1 complex-AMPK pathway: the tree that hides the forest.
Fam Cancer. 2011; 10(3):415-24 [PubMed] Free Access to Full Article Related Publications
Initially identified as the Caenorhabditis elegans PAR-4 homologue, the serine threonine kinase LKB1 is conserved throughout evolution and ubiquitously expressed. In humans, LKB1 is causally linked to the Peutz-Jeghers syndrome and is one of the most commonly mutated genes in several cancers like lung and cervical carcinomas. These observations have led to classify LKB1 as tumour suppressor gene. Although, considerable dark zones remain, an impressive leap in the understanding of LKB1 functions has been done during the last decade. Role of LKB1 as a major actor of the AMPK/mTOR pathway connecting cellular metabolism, cell growth and tumorigenesis has been extensively studied probably to the detriment of other functions of equal importance. This review will discuss about LKB1 activity regulation, its effectors and clues on their involvement in cell polarity.

Related: Cancer Prevention and Risk Reduction


Zhang Y, Yu G, Jiang P, et al.
Decreased expression of protease-activated receptor 4 in human gastric cancer.
Int J Biochem Cell Biol. 2011; 43(9):1277-83 [PubMed] Related Publications
Protease-activated receptors (PARs) are a unique family of G-protein coupled receptors. PAR4, the most recently identified PAR member, was reported to be overexpressed during the progression of colon and prostate cancers. Though PAR4 mRNA was detected in normal stomach, the role of PAR4 in gastric cancer has not been investigated. In this study, differential expression of PAR4 was measured by real-time PCR (n=28) and tissue microarrays (n=74). We showed that PAR4 was located from basal to middle portions of normal gastric mucosa. PAR4 expression was remarkably decreased in gastric cancer tissues as compared with matched noncancerous tissues, especially in positive lymph node or low differentiation cancers. Furthermore, methylation of the PAR4 promoter in cell lines was assessed by treatment with 5-aza-2'-deoxycytidine and genomic bisulfite sequencing. AGS and N87 human gastric cancer cell lines did not express PAR4, as compared to HT-29 human colon cancer cell line with significant PAR4 expression. Treatment with 5-aza-2'-deoxycytidine restored PAR4 expression in AGS and N87 cells, which exhibited significantly more 5-methylcytosines in the PAR4 promoter compared with HT-29 cells. Our results revealed that down-regulation of PAR4 expression occurs frequently in gastric cancers and exhibits association with more aggressive gastric cancer. Interestingly, the loss of PAR4 expression in gastric cancers may result from hypermethylation of the PAR4 promoter.

Related: Azacitidine Stomach Cancer Gastric Cancer


Casolari DA, Pereira MC, de Bessa Garcia SA, Nagai MA
Insulin-like growth factor-1 and 17β-estradiol down-regulate prostate apoptosis response-4 expression in MCF-7 breast cancer cells.
Int J Mol Med. 2011; 28(3):337-42 [PubMed] Related Publications
The PKC apoptosis WT1 regulator gene, also named prostate apoptosis response-4 (PAR-4), encodes a pro-apoptotic protein that sensitizes cells to numerous apoptotic stimuli. Insulin-like growth factor-1 (IGF-1) and 17β-estradiol (E2), two important factors for breast cancer development and progression, have been shown to down-regulate PAR-4 expression and inhibit apoptosis induced by PAR-4 in neuronal cells. In this study, we sought to investigate the mechanisms of regulation of PAR-4 gene expression in MCF-7 cells treated with E2 or IGF-1. E2 (10 nM) and IGF-1 (12.5 nM) each down-regulated PAR-4 expression in MCF-7 cells after 24 h of treatment. The effect of E2 was dependent on ER activation, as demonstrated by an increase in PAR-4 expression when cells were pretreated for 1 h with 1 µM ICI-182,780 (ICI) before receiving E2 plus ICI. The effect of IGF-1 was abolished by pre-treatment for 1 h with 30 µM LY294002 (a specific PI3-K inhibitor), and significantly inhibited by 30 µM SB202190 (a specific p38MAPK inhibitor). We also demonstrated that E2 acts synergistically with IGF-1, resulting in greater down-regulation of PAR-4 mRNA expression compared with E2 or IGF-1 alone. Our results show for the first time that E2 and IGF-1 inhibit PAR-4 gene expression in MCF-7 cells, suggesting that this down-regulation may provide a selective advantage for breast cancer cell survival.

Related: Apoptosis Breast Cancer IGF1


Sharma AK, Kline CL, Berg A, et al.
The Akt inhibitor ISC-4 activates prostate apoptosis response protein-4 and reduces colon tumor growth in a nude mouse model.
Clin Cancer Res. 2011; 17(13):4474-83 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy; however, Akt1 inactivates Par-4. Previously we showed that Par-4-overexpressing colon cancer cells responded more readily to 5-fluorouracil (5-FU) than their wild-type counterparts. In this study we investigated (i) the effects of the Akt inhibitor, phenylbutyl isoselenocyanate (ISC-4), on tumor growth in nude mice and (ii) bystander effect of Par-4-overexpressing cells on wild-type tumor growth.
EXPERIMENTAL DESIGN: Mice (n = 80) were injected with wild-type HT29 human colon cancer cells in the right flank. Forty of the mice were also injected in the left flank with HT29 cells engineered to overexpress Par-4. The mice were treated with 5-FU, ISC-4, a combination, or vehicle.
RESULTS: ISC-4 reduced tumor growth, with or without 5-FU. When Par-4-overexpressing tumors were present, wild-type tumors grew more slowly compared to when no Par-4-overexpressing tumors were present. The level of Par-4 protein as well as the Par-4 binding protein, GRP78, was increased in wild-type cells growing in the same mouse as Par-4-overexpressing tumors compared with wild-type tumors growing without Par-4-overexpressing tumors.
CONCLUSIONS: Par-4-overexpressing tumors exhibited a bystander effect on wild-type tumors growing distally in the same mouse. This suggests that gene therapy need not achieve total penetration to have a positive effect on tumor treatment. Inhibition of Akt with ISC-4 inhibited tumor growth and had a greater effect on cells overexpressing Par-4. The data indicate ISC-4 alone or in combination with Par-4 can greatly reduce tumor growth.

Related: Apoptosis AKT1 Signal Transduction


Bonilla C, Hooker S, Mason T, et al.
Prostate cancer susceptibility Loci identified on chromosome 12 in African Americans.
PLoS One. 2011; 6(2):e16044 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is a complex disease that disproportionately affects African Americans and other individuals of African descent. A number of regions across the genome have been associated to PCa, most of them with moderate effects. A few studies have reported chromosomal changes on 12p and 12q that occur during the onset and development of PCa but to date no consistent association of the disease with chromosome 12 polymorphic variation has been identified. In order to unravel genetic risk factors that underlie PCa health disparities we investigated chromosome 12 using ancestry informative markers (AIMs), which allow us to distinguish genomic regions of European or West African origin, and tested them for association with PCa. Additional SNPs were genotyped in those areas where significant signals of association were detected. The strongest signal was discovered at the SNP rs12827748, located upstream of the PAWR gene, a tumor suppressor, which is amply expressed in the prostate. The most frequent allele in Europeans was the risk allele among African Americans. We also examined vitamin D related genes, VDR and CYP27B1, and found a significant association of PCa with the TaqI polymorphism (rs731236) in the former. Although our results warrant further investigation we have uncovered a genetic susceptibility factor for PCa in a likely candidate by means of an approach that takes advantage of the differential contribution of parental groups to an admixed population.

Related: Chromosome 12 Prostate Cancer


Mehrotra A, Kaul D, Joshi K
LXR-α selectively reprogrammes cancer cells to enter into apoptosis.
Mol Cell Biochem. 2011; 349(1-2):41-55 [PubMed] Related Publications
There exists a general recognition of the fact that LXR-α, being a member of the nuclear receptor family, plays a crucial role in the biological process that connects inflammation, cholesterol homeostasis, and cellular decisions. In this context the present study was addressed to understand the role of LXR-α gene in the selective and specific reprogramming of cancer cells into a state of apoptosis leaving the normal cells unaffected. The results of this study revealed that LXR-α gene when activated in cancerous cells of diverse origin results in the regulation of genes coding for Bcl-2, AATF, and Par-4 in a fashion, forcing these cells to enter into the state of apoptosis leaving the normal cells unaffected. On the basis of this study we propose that in near future LXR-α agonist (Withaferin A) may definitely find its use in the therapeutic interventions directed towards the treatment of cancer.

Related: Apoptosis E2F1 Transcription Factor Cancer Prevention and Risk Reduction Signal Transduction


Rossi V, Bellastella G, De Rosa C, et al.
Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptor α and β.
J Cell Physiol. 2011; 226(5):1334-9 [PubMed] Related Publications
Raloxifene (RAL), a selective estrogen receptor (ER) modulator (SERM) seems to induce apoptosis in both androgen-dependent and -independent prostate cell (PC) lines via activation of ERβ and an antagonistic effect on ERα. In this study, we evaluated the effects of RAL on epithelial PC growth using the two following in vitro models: the androgen-dependent cell line EPN which expressed both ERs; and a stabilized epithelial cell line derived from a prostate cancer specimen (CPEC), which expressed low levels of ERβ and lacked ERα. In EPN cells, there was an increase in the pre-G1 apoptotic peak and a reduction in the S phase of the cell cycle with G0/G1 arrest after E2 or RAL treatment; bcl-2 mRNA and Bcl-2 protein levels were significantly reduced, while activated caspase-3 and Par-4 levels increased significantly after either E2 or RAL treatment; in addition, c-myc transcript was inhibited after 10(-6)  M RAL treatment. A dose-dependent increase of metallothionein II gene RNA level was also induced by RAL in EPN. In CPEC, there was only a weak apoptotic peak associated with caspase-3 activation and Par-4 increase after either E2 or RAL treatment; while c-myc transcript level increased. RAL induced a rapid but transient phosphorylation of ERK 1/2 in EPN cells but generated a sustained effect in CPEC. These findings suggest that RAL effects on PC growth control in vitro are cell-specific, depending on ERβ or ERβ/ERα relative expression levels. Moreover, this study demonstrated that RAL affected both transcriptional regulation and non-genomic signals, which resulted in the modulation of multiple signaling pathways of apoptosis and of cell cycle progression.

Related: Apoptosis CASP3 Prostate Cancer Signal Transduction


Xu X, Omelchenko T, Hall A
LKB1 tumor suppressor protein regulates actin filament assembly through Rho and its exchange factor Dbl independently of kinase activity.
BMC Cell Biol. 2010; 11:77 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Germline mutations in LKB1 result in Peutz-Jeghers Syndrome characterized by intestinal hamartomas and increased incidence of epithelial cancers. LKB1 encodes a serine/threonine kinase that plays an important role in regulating energy metabolism through the AMPK/mTOR signaling pathway. In addition, LKB1 is homologous to PAR-4, a polarity protein first described in C. elegans, while activation of LKB1 in mammalian epithelial cells induces the polarized assembly of actin filaments.
RESULTS: To explore the mechanism by which LKB1 interacts with the actin cytoskeleton, we introduced LKB1 into HeLa cells that lack endogenous LKB1. This results in activation of the small GTPase Rho and the assembly of linear actin filaments associated with focal adhesions. These effects on the actin cytoskeleton are attenuated by siRNA-mediated depletion of the guanine nucleotide exchange factor Dbl. Co-expression of the LKB1 with the adaptor protein STRAD induces actin filament puncta associated with phospho-ezrin.
CONCLUSIONS: This study reveals that LKB1 regulates the actin cytoskeleton through a Dbl/Rho pathway.

Related: Signal Transduction


Raina A, Kaul D
LXR-α genomics programmes neuronal death observed in Alzheimer's disease.
Apoptosis. 2010; 15(12):1461-9 [PubMed] Related Publications
Keeping in view the fact that the most pathognomonic feature of Alzheimer's disease is the abnormal processing of neuronal cell membrane amyloid precursor protein accompanied by significantly elevated human serum and CSF levels of 24-hydroxycholesterol recognised widely as the specific endogenous ligand of Liver X receptor (LXR-α), the present study was addressed to explore the epigenomic-pathway (if any) that connects LXR-α activation with the genes recognised to be involved in the regulation of aberrant Abeta production leading to the generation of toxic and inflammatory mediators responsible for neuronal death. The results of such a study revealed that LXR-α activation by its specific endogenous or exogenous ligands within neuroblastoma cells resulted in the over-expression of PAR-4 gene accompanied by suppression of AATF gene through its inherent capacity to regulate genes coding for SREBP and NF-κB. Over-expression of PAR-4 gene was accompanied by aberrant Abeta production followed by ROS generation and subsequent death of neuroblastoma cells used in the present study as a cellular model for neurons. Further based upon these results, it was proposed that Abeta-induced heme oxygenase-1 can ensure cholesterol-oxidation to provide endogenous ligands for the sustained activation of neuronal LXR-α dependent epigenomic-pathway leading to neuronal death observed in Alzheimer's disease.

Related: Apoptosis Neuroblastoma


Daigeler A, Chromik AM, Haendschke K, et al.
Synergistic effects of sonoporation and taurolidin/TRAIL on apoptosis in human fibrosarcoma.
Ultrasound Med Biol. 2010; 36(11):1893-906 [PubMed] Related Publications
Sonodynamic therapy, in combination with ultrasound contrast agents, proved to enhance the uptake of chemotherapeutics in malignant cells. HT1080 fibrosarcoma cells were treated in vitro with a combination of ultrasound SonoVue™-microbubbles and taurolidine (TRD) plus tumor necrosis factor related apoptosis inducing ligand (TRAIL). Apoptosis was measured by TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay and fluorescence activated cell sorting (FACS) analysis. Gene expression was analysed by RNA-microarray. The apoptotic effects of TRD and TRAIL on human fibrosarcoma are enhanced by sonodynamic therapy and additional application of contrast agents, such as SonoVue™ by 25%. A broad change in the expression of genes related to apoptotic pathways is observed when ultrasound and microbubbles act synchronously in combination with the chemotherapeutics (e.g. BIRC3, NFKBIA and TNFAIP3). Some of these genes have already been proven to play a role in programmed cell death in human fibrosarcoma (HSPA1A/HSPA1B, APAF1, PAWR, SOCS2) or were associated with sonication induced apoptosis (CD44). Further studies are needed to explore the options of sonodynamic therapy on soft tissue sarcoma and its molecular mechanisms.

Related: Apoptosis


Chang LH, Chen CH, Huang DY, et al.
Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1α translational pathway in colorectal cancer cells.
J Cell Physiol. 2011; 226(4):1060-8 [PubMed] Related Publications
Deep vein thrombosis associated with advanced cancer is known as Trousseau's syndrome. We hypothesized that thrombin, an activator of protease-activated receptor (PAR)-1 and PAR-4 contributes to tumor metastasis. In this study, we demonstrated that thrombin and the PAR-1 activating peptide (AP) SFLLRN, but not the PAR-4 AP GYPGKF, induced HIF-1α activities, protein expression, and cell motility in colorectal cancer cells, and these actions were significantly inhibited by the PAR-1 antagonist SCH79797. Moreover, thrombin-induced HIF-1α activity and cell motility were blocked by inhibiting important mediators of signaling transduction, including the ERK, PI3K, and mTOR pathways. These results showed that thrombin induced HIF-1α protein expression through PAR-1 and HIF-1α translational de novo protein synthesis. Twist can regulate epithelial-mesenchymal transition (EMT) and increase tumor metastasis. However, we observed that thrombin-induced HIF-1α increased Twist mRNA and its protein level was mediated by the modulation of PAR-1 activation and the HIF-1α translational pathway. In addition, Twist could increase N-cadherin but not E-cadherin to promote tumor metastasis. Overexpression of dominant-negative HIF-1α reversed thrombin-mediated Twist and Twist-induced N-cadherin expression. Moreover, siTwist inhibited Twist-induced N-cadherin and Thrombin-induced cell motility. In conclusion, our study showed that thrombin-induced HIF-1α upregulated Twist at the transcriptional level to enhance cell motility. These findings show that thrombin upregulates Twist via HIF-1α to make tumor cells malignant and also establish a link between the coagulation disorder and cancer metastasis.

Related: Colorectal (Bowel) Cancer HIF1A AKT1 Signal Transduction TWIST1


Franchitto A, Torrice A, Semeraro R, et al.
Prostate apoptosis response-4 is expressed in normal cholangiocytes, is down-regulated in human cholangiocarcinoma, and promotes apoptosis of neoplastic cholangiocytes when induced pharmacologically.
Am J Pathol. 2010; 177(4):1779-90 [PubMed] Free Access to Full Article Related Publications
Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that sensitizes cells to apoptosis; therefore, Par-4 modulation has therapeutic potential. No data currently exist on Par-4 expression in cholangiocarcinoma (CCA). We evaluated the expression of Par-4 in normal and neoplastic cholangiocytes and the effects of its pharmacological or genetic modulation. The study was performed in human and rat liver, CCA patient biopsies, and two CCA cell lines. PAR-4 was expressed in normal rat and human cholangiocytes, but its expression levels decreased in both human CCA and CCA cell lines. In both intrahepatic and extrahepatic CCA, Par-4 expression (as shown by immunohistochemistry) was inversely correlated with markers of proliferation (eg, proliferating cellular nuclear antigen) and directly correlated with apoptotic markers (eg, Bax and Bax/BCL2 ratio). Par-4 expression was decreased during CCA cell proliferation but was enhanced after apoptosis induction. Pharmacological induction of Par-4 expression in CCA cell lines by diindolymethane or withaferin A promoted activation of apoptosis and inhibition of proliferation. In contrast, specific Par-4 silencing by small-interfering RNA determined activation of CCA cell line proliferation. Par-4 is expressed in rat and human cholangiocytes and is down-regulated in both human CCA and CCA cell lines. Par-4 protein levels decrease during cell proliferation but increase during apoptosis. Pharmacological or genetic induction of Par-4 determines apoptosis of CCA cells, suggesting Par-4 targeting as a CCA treatment strategy.

Related: Apoptosis


Nagai MA, Gerhard R, Salaorni S, et al.
Down-regulation of the candidate tumor suppressor gene PAR-4 is associated with poor prognosis in breast cancer.
Int J Oncol. 2010; 37(1):41-9 [PubMed] Related Publications
Substantial experimental evidence indicates that PAWR gene (PKC apoptosis WT1 regulator; also named PAR-4, prostate apoptosis response-4) is a central player in cancer cell survival and a potential target for cancer-selective targeted therapeutics. However, little is known about the role of PAR-4 in breast cancer. We investigated the possible role of PAR-4 expression in breast cancer. IHC results on tissue microarrays containing 1,161 primary breast tumor samples showed that 57% (571/995) of analyzable cases were negative for PAR-4 nuclear staining. Down-regulation of nuclear PAR-4 protein expression predicted a poor prognosis for breast cancer patients (OS; P=0.041, log-rank test). PAR-4 down-regulation also correlates with poor survival in the group of patients with luminal A subtype breast cancer (P=0.028). Additionally, in this large series of breast cancer patients, we show that ERBB2/HER2, EGFR and pAKT protein expression are significantly associated with shorter disease-free survival and overall survival, but the prognosis was even worse for HER2-positive, EGFR-positive or pAKT-positive breast cancer patients with tumors negative for nuclear PAR-4 expression. Furthermore, using three-dimensional (3D) cell culture we provide preliminary results showing that PAR-4 is highly expressed in the MCF10A cells inside the acini structure, suggesting that PAR-4 might have a role in the lumen acini formation. Taken together, our results provide, for the first time, evidence that PAR-4 may have a role in the process of the mammary gland morphogenesis and its functional inactivation is associated with tumor aggressive phenotype and might represent an additional prognostic and predictive marker for breast cancer.

Related: Breast Cancer


Wang BD, Kline CL, Pastor DM, et al.
Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-FU through mediation of an NF kappaB and microRNA network.
Mol Cancer. 2010; 9:98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Diminished expression or activity of prostate apoptosis response protein 4 (Par-4) has been demonstrated in a number of cancers, although reports on Par-4 expression during colon cancer progression are lacking. An understanding of the molecular events in conjunction with the genetic networks affected by Par-4 is warranted.
RESULTS: Colon cancer specimens derived from patients have significantly diminished expression of Par-4 mRNA relative to paired normal colon. Hence, the functional consequences of reintroducing Par-4 into HT29 colon cancer cells were assessed. Overexpression augmented the interaction of Par-4 with NF kappaB in the cytosol but not nucleus, and facilitated apoptosis in the presence of 5-fluorouracil (5-FU). Analogous findings were obtained when AKT1 pro-survival signaling was inhibited. Transcriptome profiling identified approximately 700 genes differentially regulated by Par-4 overexpression in HT29 cells. Nearly all Par-4-regulated genes were shown by promoter analysis to contain cis-binding sequences for NF kappaB, and meta-analysis of patient expression data revealed that one-third of these genes exist as a recurrent co-regulated network in colon cancer specimens. Sets of genes involved in programmed cell death, cell cycle regulation and interestingly the microRNA pathway were found overrepresented in the network. Noteworthy, Par-4 overexpression decreased NF kappaB occupancy at the promoter of one particular network gene DROSHA, encoding a microRNA processing enzyme. The resulting down-regulation of DROSHA was associated with expression changes in a cohort of microRNAs. Many of these microRNAs are predicted to target mRNAs encoding proteins with apoptosis-related functions. Western and functional analyses were employed to validate several predictions. For instance, miR-34a up-regulation corresponded with a down-regulation of BCL2 protein. Treating Par-4-overexpressing HT29 cells with a miR-34a antagomir functionally reversed both BCL2 down-regulation and apoptosis by 5-FU. Conversely, bypassing Par-4 overexpression by direct knockdown of DROSHA expression in native HT29 cells increased miR-34a expression and 5-FU sensitivity.
CONCLUSION: Our findings suggest that the initiation of apoptotic sensitivity in colon cancer cells can be mediated by Par-4 binding to NF kappaB in the cytoplasm with consequential changes in the expression of microRNA pathway components.

Related: Apoptosis Fluorouracil Prostate Cancer AKT1 DICER1 Signal Transduction


Donninger H, Hesson L, Vos M, et al.
The Ras effector RASSF2 controls the PAR-4 tumor suppressor.
Mol Cell Biol. 2010; 30(11):2608-20 [PubMed] Free Access to Full Article Related Publications
RASSF2 is a novel proapoptotic effector of K-Ras. Inhibition of RASSF2 expression enhances the transforming effects of K-Ras, and epigenetic inactivation of RASSF2 is frequently detected in mutant Ras-containing primary tumors. Thus, RASSF2 is implicated as a tumor suppressor whose inactivation facilitates transformation by disconnecting apoptotic responses from Ras. The mechanism of action of RASSF2 is not known. Here we show that RASSF2 forms a direct and endogenous complex with the prostate apoptosis response protein 4 (PAR-4) tumor suppressor. This interaction is regulated by K-Ras and is essential for the full apoptotic effects of PAR-4. RASSF2 is primarily a nuclear protein, and shuttling of PAR-4 from the cytoplasm to the nucleus is essential for its function. We show that RASSF2 modulates the nuclear translocation of PAR-4 in prostate tumor cells, providing a mechanism for its biological effects. Thus, we identify the first tumor suppressor signaling pathway emanating from RASSF2, we identify a novel mode of action of a RASSF protein, and we provide an explanation for the extraordinarily high frequency of RASSF2 inactivation we have observed in primary prostate tumors.

Related: Prostate Cancer Signal Transduction RASSF2


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Cite this page: Cotterill SJ. PAWR (PAR-4), Cancer Genetics Web: http://www.cancerindex.org/geneweb/PAWR.htm Accessed: date

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