Gene Summary

Gene:PRKCE; protein kinase C, epsilon
Aliases: PKCE, nPKC-epsilon
Summary:Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been shown to be involved in many different cellular functions, such as neuron channel activation, apoptosis, cardioprotection from ischemia, heat shock response, as well as insulin exocytosis. Knockout studies in mice suggest that this kinase is important for lipopolysaccharide (LPS)-mediated signaling in activated macrophages and may also play a role in controlling anxiety-like behavior. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein kinase C epsilon type
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
Show (61)
Pathways:What pathways are this gene/protein implicaed in?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 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.

  • Isoenzymes
  • MAP Kinase Signaling System
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Polymerase Chain Reaction
  • Epigenetics
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • Apoptosis
  • Protein Kinase C
  • CRAF
  • Genomics
  • Proto-Oncogene Proteins
  • MicroRNAs
  • Reproducibility of Results
  • Cell Proliferation
  • Western Blotting
  • Mitogen-Activated Protein Kinases
  • Transcriptional Activation
  • DNA-Binding Proteins
  • HEK293 Cells
  • Transfection
  • NF-kappa B
  • Mutation
  • Transcription Factors
  • Promoter Regions
  • Chromosome 2
  • Enzymologic Gene Expression Regulation
  • Brain, Astrocytoma, Childhood
  • Enzyme Activation
  • Phosphorylation
  • Breast Cancer
  • Nucleic Acid Hybridization
  • Protein Kinase C-epsilon
  • Transcription
  • ras Proteins
  • Cell Division
  • Up-Regulation
  • Protein Kinase C-alpha
  • RNA Interference
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: PRKCE (cancer-related)

Brownlow N, Pike T, Zicha D, et al.
Mitotic catenation is monitored and resolved by a PKCε-regulated pathway.
Nat Commun. 2014; 5:5685 [PubMed] Free Access to Full Article Related Publications
Exit from mitosis is controlled by silencing of the spindle assembly checkpoint (SAC). It is important that preceding exit, all sister chromatid pairs are correctly bioriented, and that residual catenation is resolved, permitting complete sister chromatid separation in the ensuing anaphase. Here we determine that the metaphase response to catenation in mammalian cells operates through PKCε. The PKCε-controlled pathway regulates exit from the SAC only when mitotic cells are challenged by retained catenation and this delayed exit is characterized by BubR1-high and Mad2-low kinetochores. In addition, we show that this pathway is necessary to facilitate resolution of retained catenanes in mitosis. When delayed by catenation in mitosis, inhibition of PKCε results in premature entry into anaphase with PICH-positive strands and chromosome bridging. These findings demonstrate the importance of PKCε-mediated regulation in protection from loss of chromosome integrity in cells failing to resolve catenation in G2.

Murray JC, Aldeghaither D, Wang S, et al.
c-Abl modulates tumor cell sensitivity to antibody-dependent cellular cytotoxicity.
Cancer Immunol Res. 2014; 2(12):1186-98 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Monoclonal antibodies (mAb) can modulate cancer cell signal transduction and recruit antitumor immune effector mechanisms-including antibody-dependent cellular cytotoxicity (ADCC). Although several clinically effective antibodies can promote ADCC, therapeutic resistance is common. We hypothesized that oncogenic signaling networks within tumor cells affect their sensitivity to ADCC. We developed a screening platform and targeted 60 genes derived from an EGFR gene network using RNAi in an in vitro ADCC model system. Knockdown of GRB7, PRKCE, and ABL1 enhanced ADCC by primary and secondary screens. ABL1 knockdown also reduced cell proliferation, independent of its ADCC enhancement effects. c-Abl overexpression decreased ADCC sensitivity and rescued the effects of ABL1 knockdown. Imatinib inhibition of c-Abl kinase activity also enhanced ADCC-phenocopying ABL1 knockdown-against several EGFR-expressing head-and-neck squamous cell carcinoma cell lines by ex vivo primary natural killer cells. Our findings suggest that combining c-Abl inhibition with ADCC-promoting antibodies, such as cetuximab, could translate into increased therapeutic efficacy of mAbs.

Park YS, Kang JW, Lee DH, et al.
Interleukin-32α downregulates the activity of the B-cell CLL/lymphoma 6 protein by inhibiting protein kinase Cε-dependent SUMO-2 modification.
Oncotarget. 2014; 5(18):8765-77 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
A proinflammatory cytokine IL-32 acts as an intracellular mediator. IL-32α interacts with many intracellular molecules, but there are no reports of interaction with a transcriptional repressor BCL6. In this study, we showed that PMA induces an interaction between IL-32α, PKCε, and BCL6, forming a trimer. To identify the mechanism of the interaction, we treated cells with various inhibitors. In HEK293 and THP-1 cell lines, treatment with a pan-PKC inhibitor, PKCε inhibitor, and PKCδ inhibitor decreased BCL6 and IL-32α protein expression. MAPK inhibitors and classical PKC inhibitor did not decrease PMA-induced BCL6 and IL-32α protein expression. Further, the pan-PKC inhibitor and PKCε inhibitor disrupted PMA-induced interaction between IL-32α and BCL6. These data demonstrate that the intracellular interaction between IL-32α and BCL6 is induced by PMA-activated PKCε. PMA induces post-translational modification of BCL6 by conjugation to SUMO-2, while IL-32α inhibits. PKCε inhibition eliminated PMA-induced SUMOylation of BCL6. Inhibition of BCL6 SUMOylation by IL-32α affected the cellular function and activity of the transcriptional repressor BCL6 in THP-1 cells. Thus, we showed that IL-32α is a negative regulator of the transcriptional repressor BCL6. IL-32α inhibits BCL6 SUMOylation by activating PKCε, resulting in the modulation of BCL6 target genes and cellular functions of BCL6.

Pu X, Wang L, Chang JY, et al.
Inflammation-related genetic variants predict toxicity following definitive radiotherapy for lung cancer.
Clin Pharmacol Ther. 2014; 96(5):609-15 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Definitive radiotherapy improves locoregional control and survival in inoperable non-small cell lung cancer patients. However, radiation-induced toxicities (pneumonitis/esophagitis) are common dose-limiting inflammatory conditions. We therefore conducted a pathway-based analysis to identify inflammation-related single-nucleotide polymorphisms associated with radiation-induced pneumonitis or esophagitis. A total of 11,930 single-nucleotide polymorphisms were genotyped in 201 stage I-III non-small cell lung cancer patients treated with definitive radiotherapy. Validation was performed in an additional 220 non-small cell lung cancer cases. After validation, 19 single-nucleotide polymorphisms remained significant. A polygenic risk score was generated to summarize the effect from validated single-nucleotide polymorphisms. Significant improvements in discriminative ability were observed when the polygenic risk score was added into the clinical/epidemiological variable-based model. We then used 277 lymphoblastoid cell lines to assess radiation sensitivity and expression quantitative trait loci (eQTL) relationships of the identified single-nucleotide polymorphisms. Three genes (PRKCE, DDX58, and TNFSF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities.

Wang H, Gutierrez-Uzquiza A, Garg R, et al.
Transcriptional regulation of oncogenic protein kinase Cϵ (PKCϵ) by STAT1 and Sp1 proteins.
J Biol Chem. 2014; 289(28):19823-38 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Overexpression of PKCϵ, a kinase associated with tumor aggressiveness and widely implicated in malignant transformation and metastasis, is a hallmark of multiple cancers, including mammary, prostate, and lung cancer. To characterize the mechanisms that control PKCϵ expression and its up-regulation in cancer, we cloned an ∼ 1.6-kb promoter segment of the human PKCϵ gene (PRKCE) that displays elevated transcriptional activity in cancer cells. A comprehensive deletional analysis established two regions rich in Sp1 and STAT1 sites located between -777 and -105 bp (region A) and -921 and -796 bp (region B), respectively, as responsible for the high transcriptional activity observed in cancer cells. A more detailed mutagenesis analysis followed by EMSA and ChIP identified Sp1 sites in positions -668/-659 and -269/-247 as well as STAT1 sites in positions -880/-869 and -793/-782 as the elements responsible for elevated promoter activity in breast cancer cells relative to normal mammary epithelial cells. RNAi silencing of Sp1 and STAT1 in breast cancer cells reduced PKCϵ mRNA and protein expression, as well as PRKCE promoter activity. Moreover, a strong correlation was found between PKCϵ and phospho-Ser-727 (active) STAT1 levels in breast cancer cells. Our results may have significant implications for the development of approaches to target PKCϵ and its effectors in cancer therapeutics.

Zhang X, Li D, Li M, et al.
MicroRNA-146a targets PRKCE to modulate papillary thyroid tumor development.
Int J Cancer. 2014; 134(2):257-67 [PubMed] Related Publications
MicroRNAs are single-stranded noncoding RNAs composed of approximately 22 nucleotides that suppress gene expression by selectively binding via base-pairing to the complementary 3'-untranslated region (3'-UTR) of messenger RNA transcripts. Protein kinase C epsilon (PKCε) is an important modulating member of the transducing Ras/Raf-1 signal pathway; a computational search revealed miR-146a putatively binds to the 3'-UTR of the PRKCE gene, and thus decreasing PKCε expression. Moreover, PKCε inhibits mitochondrial apoptosis and is associated with the Bcl family. However, it has been previously reported that miR-146a expression in papillary thyroid carcinoma (PTC) is slightly elevated. Thus, we hypothesized that because miR-146a expression depends on nuclear factor kappaB (NF-κB) activation and NF-κB expression is elevated in PTC, miR-146a is potentially upregulated in PTC via negative feedback of NF-κB, and thus suppressing PKCε expression. In our study, we investigated whether overexpression of miR-146a, a tumor-suppressing-miR, in PTC cells decreases cell survival and induces apoptosis. Luciferase reporter assay analysis confirmed the direct binding of miR-146a and PRKCE 3'-UTR. Specific overexpression of exogenous miR-146a significantly decreased PKCε levels in PTC cell line NPA-187 and increased apoptosis. Additionally, using stably expressing miR-146a thyroid carcinoma cells to establish subcutaneous tumors, the tumor growth exhibited significant inhibition. Our study confirmed the tumor-suppressing role of miR-146a in thyroid carcinoma cells and contributes to the knowledge regarding modulation of Ras/Raf-1 signal transduction and apoptosis via PKCε targeted by miR-146a in PTC; moreover, our findings confirmed that miR-146a is involved in the feedback system of the classical NF-κB signal pathway in PTC.

Körner C, Keklikoglou I, Bender C, et al.
MicroRNA-31 sensitizes human breast cells to apoptosis by direct targeting of protein kinase C epsilon (PKCepsilon).
J Biol Chem. 2013; 288(12):8750-61 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
MicroRNAs post-transcriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular phenotypes, including cell proliferation, cell motility, apoptosis, and stress response. In breast cancer cell systems, miR-31 has been shown to inhibit cell migration, invasion, and metastasis. Here, we link enhanced expression of miR-31 to the inhibition of the oncogenic NF-κB pathway, thus supporting the tumor-suppressive function of this microRNA. We identified protein kinase C epsilon (PKCε encoded by the PRKCE gene) as a novel direct target of miR-31 and show that down-regulation of PKCε results in impaired NF-κB signaling, enhanced apoptosis, and increased sensitivity of MCF10A breast epithelial and MDA-MB-231 triple-negative breast cancer cells toward ionizing radiation as well as treatment with chemotherapeutics. Mechanistically, we attribute this sensitization to anti-cancer treatments to the PRKCE-mediated down-regulation of the anti-apoptotic factor BCL2. In clinical breast cancer samples, high BCL2 expression was associated with poor prognosis. Furthermore, we found an inverse correlation between miR-31 and BCL2 expression, highlighting the functional relevance of the indirect down-regulation of BCL2 via direct targeting of PRKCE by miR-31.

Yang W, Xia Y, Cao Y, et al.
EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis.
Mol Cell. 2012; 48(5):771-84 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Many types of human tumor cells have overexpressed pyruvate kinase M2 (PKM2). However, the mechanism underlying this increased PKM2 expression remains to be defined. We demonstrate here that EGFR activation induces PLCγ1-dependent PKCε monoubiquitylation at Lys321 mediated by RINCK1 ubiquitin ligase. Monoubiquitylated PKCε interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKCε phosphorylates IKKβ at Ser177 and activates IKKβ. Activated RelA interacts with HIF1α, which is required for RelA to bind the PKM promoter. PKCε- and NF-κB-dependent PKM2 upregulation is required for EGFR-promoted glycolysis and tumorigenesis. In addition, PKM2 expression correlates with EGFR and IKKβ activity in human glioblastoma specimens and with grade of glioma malignancy. These findings highlight the distinct regulation of NF-κB by EGF, in contrast to TNF-α, and the importance of the metabolic cooperation between the EGFR and NF-κB pathways in PKM2 upregulation and tumorigenesis.

Wang W, Corrigan-Cummins M, Hudson J, et al.
MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response.
Haematologica. 2012; 97(4):586-94 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma.
DESIGN AND METHODS: MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human microRNAs. Tandem gene expression profiles were obtained for predicting microRNA targets.
RESULTS: The expression of 133 microRNAs was significantly different (> 2-fold; P<0.05) between follicular lymphoma and follicular hyperplasia. Forty-four microRNAs in three groups generated a unique follicular lymphoma signature. Of these, ten microRNAs were increased (miR-193a-5p, -193b*, -345, -513b, -574-3p, -584, -663, -1287, -1295, and -1471), 11 microRNAs were decreased (miR-17*, -30a, -33a, -106a*, -141, -202, -205, -222, -301b, -431*, and -570), and 23 microRNAs formed a group that was increased in most cases of follicular lymphoma but showed lower expression in a subset of cases (let-7a, let-7f, miR-7-1*, -9, -9*, -20a, -20b, -30b, -96, -98, -194, -195, -221*, -374a, -374b, -451, -454, -502-3p, -532-3p, -664*, -1274a, -1274b, and -1260). Higher expression of this last group was associated with improved response to chemotherapy. Gene expression analysis revealed increased expression of MAPK1, AKT1, PRKCE, IL4R and DROSHA and decreased expression of CDKN1A/p21, SOCS2, CHEK1, RAD51, KLF4, BLIMP1 and IRF4 in follicular lymphoma. Functional studies indicated that CDKN1A/p21 and SOCS2 expression is directly regulated by miR-20a/-20b and miR-194, respectively.
CONCLUSIONS: Follicular lymphoma is characterized by a unique microRNA signature, containing a subset of microRNAs whose expression correlate with response to chemotherapy. miR-20a/b and miR-194 target CDKN1A and SOCS2 in follicular lymphoma, potentially contributing to tumor cell proliferation and survival.

Kilpinen S, Ojala K, Kallioniemi O
Analysis of kinase gene expression patterns across 5681 human tissue samples reveals functional genomic taxonomy of the kinome.
PLoS One. 2010; 5(12):e15068 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Kinases play key roles in cell signaling and represent major targets for drug development, but the regulation of their activation and their associations with health and disease have not been systematically analyzed. Here, we carried out a bioinformatic analysis of the expression levels of 459 human kinase genes in 5681 samples consisting of 44 healthy and 55 malignant human tissues. Defining the tissues where the kinase genes were transcriptionally active led to a functional genomic taxonomy of the kinome and a classification of human tissues and disease types based on the similarity of their kinome gene expression. The co-expression network around each of the kinase genes was defined in order to determine the functional context, i.e. the biological processes that were active in the cells and tissues where the kinase gene was expressed. Strong associations for individual kinases were found for mitosis (69 genes, including AURKA and BUB1), cell cycle control (73 genes, including PLK1 and AURKB), DNA repair (49 genes, including CHEK1 and ATR), immune response (72 genes, including MATK), neuronal (131 genes, including PRKCE) and muscular (72 genes, including MYLK2) functions. We then analyzed which kinase genes gain or lose transcriptional activity in the development of prostate and lung cancers and elucidated the functional associations of individual cancer associated kinase genes. In summary, we report here a systematic classification of kinases based on the bioinformatic analysis of their expression in human tissues and diseases, as well as grouping of tissues and tumor types according to the similarity of their kinome transcription.

Peng Y, Hu Y, Feng N, et al.
L-3-n-butyl-phthalide alleviates hydrogen peroxide-induced apoptosis by PKC pathway in human neuroblastoma SK-N-SH cells.
Naunyn Schmiedebergs Arch Pharmacol. 2011; 383(1):91-9 [PubMed] Related Publications
Alzheimer's disease (AD) is the most common form of dementia. Oxidative stress is one of the earliest events in the neurological and pathological changes of AD. L-3-n-butyl-phthalide (L-NBP), an anti-cerebral ischemia agent, has been shown a potential in AD treatment. In this study, we investigated the neuroprotective effect of L-NBP on hydrogen peroxide (H₂O₂)-induced apoptosis in human neuroblastoma SK-N-SH cells. H₂O₂ significantly reduced cell viability and increased the number of apoptotic-like cells, indicating that H₂O₂ induced neurotoxicity. In addition, real-time PCR and western blot studies showed that Bcl-2 and Bcl-w expressions were decreased, and Bax expression was increased with H₂O₂ treatment. Moreover, protein kinase C (PKC) α expression was down-regulated after H₂O₂ treatment. All of these phenotypes induced by H₂O₂ were markedly reversed by L-NBP. Pretreatment with L-NBP significantly increased cell viability of H₂O₂-damaged cells, and reduced H₂O₂-induced neuronal apoptosis. L-NBP treatment at dose of 10 μM inhibited H₂O₂-induced down-regulation of Bcl-2, Bcl-w, and PKCα but also attenuated the overexpression of Bax. PKC inhibitor, calphostin C, significantly attenuated the protective effects of L-NBP. Our findings suggest that L-NBP may protect neurons against H₂O₂-induced apoptosis by modulating apoptosis-related genes and activating PKCα pathway.

Gromova P, Ralea S, Lefort A, et al.
Kit K641E oncogene up-regulates Sprouty homolog 4 and trophoblast glycoprotein in interstitial cells of Cajal in a murine model of gastrointestinal stromal tumours.
J Cell Mol Med. 2009; 13(8A):1536-48 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Gastrointestinal stromal tumours (GIST) are thought to derive from the interstitial cells of Cajal (ICC) or an ICC precursor. Oncogenic mutations of the receptor tyrosine kinase KIT are present in most GIST. KIT K642E was originally identified in sporadic GIST and later found in the germ line of a familial GIST cohort. A mouse model harbouring a germline Kit K641E mutant was created to model familial GIST. The expression profile was investigated in the gastric antrum of the Kit(K641E) murine GIST model by microarray, quantitative PCR and immunofluorescence. Gja1/Cx43, Gpc6, Gpr133, Pacrg, Pde3a, Prkar2b, Prkcq/Pkce, Rasd2, Spry4 and Tpbg/5T4 were found to be up-regulated. The proteins encoded by Gja1/Cx43, Pde3a, Prkcq/Pkce were localized in Kit-ir ICC in wild-type and Kit(K641E) animals while Spry4 and Tpbg/5T4 were detected in Kit-ir cells only in Kit(K641E), but not in Kit(WT/WT) animals. Most up-regulated genes in this mouse model belong to the gene expression profile of human GIST but also to the profile of normal Kit(+) ICC in the mouse small intestine. Spry4 and Tpbg/5T4 may represent candidates for targeted therapeutic approaches in GIST with oncogenic KIT mutations.

Hakimuddin F, Tiwari K, Paliyath G, Meckling K
Grape and wine polyphenols down-regulate the expression of signal transduction genes and inhibit the growth of estrogen receptor-negative MDA-MB231 tumors in nu/nu mouse xenografts.
Nutr Res. 2008; 28(10):702-13 [PubMed] Related Publications
The antitumor properties of the Merlot grape (and Merlot wine) polyphenols were evaluated in relation to their ability to modulate gene expression in developing tumors using an athymic nude mouse model transplanted with the estrogen receptor-negative MDA-MB231 cells. Groups of mice were fed a modified AIN 93G diet (Research Diets Inc, New Brunswick, NJ) with the experimental groups receiving 100 mg/kg body weight equivalent of polyphenols by gavage 3 times per week. After 1 week of acclimation and another week of polyphenol supplementation, MDA-MB231 cells were transplanted and the growth patterns of the tumors monitored. After 33 days of tumor growth, the animals were euthanized, the tumors isolated, and gene expression profiles analyzed using signal transduction and cell cycle arrays. The development of tumors was almost totally arrested in grape polyphenol-treated mice. Total polyphenols isolated from the wine were more effective in reducing tumor growth as compared with a hydrophobic polyphenol fraction isolated from the wine, showing a 50% and 60% reduction in tumor growth on day 33, respectively. Analysis of gene expression showed that genes such as CDK2, FAS, LEF1, PRKCE, and PTGS2, belonging to the NFkappaB, phospholipase C, and calcium signaling pathways, were down-regulated in tumors that developed in grape polyphenol-treated mice. Several genes related to cell cycle regulation, such as CDK5RAP1, RBBP8, and SERTAD1, were up-regulated in these tumors. Changes in the expression of these genes were less pronounced in tumors of wine polyphenol-treated mice. The study highlights the potential influences of dietary polyphenolic components on gene expression in estrogen receptor-negative tumors and its relation to inhibition of tumor growth.

Rahmatpanah FB, Carstens S, Guo J, et al.
Differential DNA methylation patterns of small B-cell lymphoma subclasses with different clinical behavior.
Leukemia. 2006; 20(10):1855-62 [PubMed] Related Publications
Non-Hodgkin's lymphoma (NHL) is a group of malignancies of the immune system with variable clinical behaviors and diverse molecular features. Despite the progress made in classification of NHLs based on classical methods, molecular classifications are a work in progress. Toward this goal, we used an array-based technique called differential methylation hybridization (DMH) to study small B-cell lymphoma (SBCL) subtypes. A total of 43 genomic DMH experiments were performed. From these results, several statistical methods were used to generate a set of differentially methylated genes for further validation. Methylation of LHX2, POU3F3, HOXC10, NRP2, PRKCE, RAMP, MLLT2, NKX6.1, LRP1B and ARF4 was validated in cell lines and patient samples and demonstrated subtype-related preferential methylation patterns. For LHX2 and LRP1B, bisulfite sequencing, real-time reverse transcriptase-polymerase chain reaction and induction of gene expression following treatment with the demethylating agent, 5'-aza-2'-deoxycytidine, were confirmed. This new epigenetic information is helping to define molecular portraits of distinct subtypes of SBCL that are not recognized by current classification systems and provides valuable potential insights into the biology of these tumors.

Saito M, Hori M, Obara Y, et al.
Neurotrophic factor production in human astrocytoma cells by 2,5,6-tribromogramine via activation of epsilon isoform of protein kinase C.
Eur J Pharm Sci. 2006; 28(4):263-71 [PubMed] Related Publications
It is known that astrocytes secrete several neurotrophic factors to promote the survival of neurons. For the treatment of neuronal disorders, low molecular weight compounds inducing neurotrophic factor synthesis are useful, because neurotrophic factors are polypeptides which cannot cross the blood brain barrier. When rat pheochromocytoma (PC-12) cells were cultivated in the medium of human astrocytoma cells (1321N1) treated with 2,5,6-tribromogramine, they differentiated to neuron-like cells possessing neurites, indicating that 2,5,6-tribromogramine released neurotrophic factors from 1321N1 cells. In fact, 2,5,6-tribromogramine increased nerve growth factor (NGF) protein synthesis and secretion through mRNA expression. 2,5,6-Tribromogramine inhibited carbachol-induced phosphoinositide hydrolysis as well as phorbol 12,13-myristate acetate did. The inhibition was recovered by bisindolylmaleimide I (GF109203X), a specific protein kinase C (PKC) inhibitor, indicating that 2,5,6-tribromogramine may activate PKC. The morphological differentiation of PC-12 cells by the medium treated with 2,5,6-tribromogramine was also reduced by GF109203X. 2,5,6-Tribromogramine translocated PKC-epsilon but not PKC-alpha or PKC-zeta, to membrane fraction from cytosol fraction. These results indicate that 2,5,6-tribromogramine promotes the synthesis and secretion of neurotrophic factors including NGF in 1321N1 cells via an activation of PKC-epsilon.

Okhrimenko H, Lu W, Xiang C, et al.
Protein kinase C-epsilon regulates the apoptosis and survival of glioma cells.
Cancer Res. 2005; 65(16):7301-9 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
In this study, we examined the role of protein kinase C (PKC)-epsilon in the apoptosis and survival of glioma cells using tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-stimulated cells and silencing of PKCepsilon expression. Treatment of glioma cells with TRAIL induced activation, caspase-dependent cleavage, and down-regulation of PKCepsilon within 3 to 5 hours of treatment. Overexpression of PKCepsilon inhibited the apoptosis induced by TRAIL, acting downstream of caspase 8 and upstream of Bid cleavage and cytochrome c release from the mitochondria. A caspase-resistant PKCepsilon mutant (D383A) was more protective than PKCepsilon, suggesting that both the cleavage of PKCepsilon and its down-regulation contributed to the apoptotic effect of TRAIL. To further study the role of PKCepsilon in glioma cell apoptosis, we employed short interfering RNAs directed against the mRNA of PKCepsilon and found that silencing of PKCepsilon expression induced apoptosis of various glioma cell lines and primary glioma cultures. To delineate the molecular mechanisms involved in the apoptosis induced by silencing of PKCepsilon, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that knockdown of PKCepsilon did not affect the expression of Bcl2 and Bax or the phosphorylation and expression of Erk1/2, c-Jun-NH2-kinase, p38, or STAT, whereas it selectively reduced the expression of AKT. Similarly, TRAIL reduced the expression of AKT in glioma cells and this decrease was abolished in cells overexpressing PKCepsilon. Our results suggest that the cleavage of PKCepsilon and its down-regulation play important roles in the apoptotic effect of TRAIL. Moreover, PKCepsilon regulates AKT expression and is essential for the survival of glioma cells.

Gillespie S, Zhang XD, Hersey P
Variable expression of protein kinase C epsilon in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis.
Mol Cancer Ther. 2005; 4(4):668-76 [PubMed] Related Publications
Protein kinase C (PKC) activation is believed to protect against apoptosis induced by death receptors. We have found however that the effect of activation of PKC on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma differs between cell lines. Pretreatment with phorbol 12-myristate 13-acetate (PMA) led to inhibition of apoptosis in the majority of the melanoma cell lines, but those with relatively low PKC epsilon expression were sensitized to TRAIL-induced apoptosis. Introduction of PKC epsilon into PKC epsilon-low cell lines reversed sensitization of the cells to TRAIL-induced apoptosis by PMA. In contrast, a dominant-negative form of PKC epsilon caused an increase in sensitivity. The changes in sensitivity to TRAIL-induced apoptosis were reflected in similar changes in conformation of Bax and its relocation from the cytosol to mitochondria. Similarly, there were concordant increases or decreases in mitochondrial release of second mitochondria-derived activator of caspase/DIABLO, activation of caspase-3, and processing of its substrates. Activation of PKC seemed to mediate its effects upstream of mitochondria but downstream of caspase-8 and Bid in that pretreatment with PMA did not cause significant changes in the expression levels of TRAIL death receptors, alterations in the levels of caspase-8 activation, or cleavage of Bid. PKC activated the anti-apoptotic extracellular signal-regulated kinase 1/2 pathway, but inhibitors of this pathway only partially reversed the protective effect of PKC against TRAIL-induced apoptosis. These results provide further insights into the variable responses of melanoma to TRAIL-induced apoptosis and may help define responsive phenotypes to treatment of melanoma with TRAIL.

Gillespie SK, Zhang XD, Hersey P
Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells.
Mol Cancer Ther. 2004; 3(12):1651-8 [PubMed] Related Publications
Ingenol 3-angelate (PEP005), one of the active ingredients in an extract from Euphorbia peplus, was shown in preclinical studies to have activity against human melanoma xenografts in nude mice. In the present study, we have tested its ability to induce the apoptosis of melanoma cells in vitro in the absence or presence of tumor necrosis factor-related apoptosis inducing ligand (TRAIL). The results showed that at relatively high concentrations (100 microg/mL), PEP005 killed melanoma cells mainly by induction of necrosis. In 20% of cell lines, evidence of apoptosis was observed. Apoptosis was caspase-dependent and associated with changes in mitochondrial membrane potential that were not inhibitable by overexpression of Bcl-2 or inhibition of caspases but were blocked by inhibition of protein kinase C (PKC). Low concentrations (1 or 10 microg/mL) of PEP005 either increased or decreased TRAIL-induced apoptosis in a cell line-dependent manner. These changes in TRAIL-induced apoptosis seemed to be due to activation of PKC and varying levels of PKC isoenzymes in different melanoma cell lines. PEP005-mediated enhancement of apoptosis seemed to be associated with low expression of the PKCepsilon isoform. These results indicate that PEP005 may enhance or inhibit sensitivity of melanoma to treatments associated with TRAIL-induced apoptosis depending on the PKC isoform content of melanoma cells.

Wu D, Thakore CU, Wescott GG, et al.
Integrin signaling links protein kinase Cepsilon to the protein kinase B/Akt survival pathway in recurrent prostate cancer cells.
Oncogene. 2004; 23(53):8659-72 [PubMed] Related Publications
Failure of hormone therapy often involves an outgrowth of protein kinase Cepsilon (PKCepsilon)-positive cells in recurrent prostate cancer. Our previous investigations have uncovered evidence of a complex signaling network operating downstream of this oncogenic protein kinase to actively advance the survival and proliferation of prostate cancer cells. In this study, we present evidence of a functional interplay among integrin receptors, PKCepsilon, and protein kinase B (PKB/Akt) in recurrent CWR-R1 prostate cancer cells. Flow cytometry and confocal microscopy provided evidence that PKCepsilon signaling promoted the assembly of matrix adhesions containing an abundance of colocalized actin filaments and beta1 integrins that exhibited an exposed activation epitope on the surface of live CWR-R1 cells. Reciprocal coimmunoprecipitations provided evidence of signaling complexes containing PKCepsilon, beta1 integrins, Src, and PKB/Akt in CWR-R1 cell cultures. An investigation into the functional significance of these interactions, and of their positive influence on beta1 integrins, demonstrated that PKCepsilon and several key components of the PKB/Akt signaling pathway remain constitutively phosphorylated/activated in adherent but not suspension cultures of PTEN-positive CWR-R1 cells. Gene transfer, antisense and pharmacological experiments provided additional support for the hypothesis that a mutually reinforcing signaling loop sustains the activation of beta1 integrins, PKCepsilon, and PKB/Akt in adherent prostate cancer cells.

Brenner W, Benzing F, Gudejko-Thiel J, et al.
Regulation of beta1 integrin expression by PKCepsilon in renal cancer cells.
Int J Oncol. 2004; 25(4):1157-63 [PubMed] Related Publications
Polarized cell movement represents an essential prerequisite for the progression and metastasis of malignant diseases. Protein kinase C (PKC) which physically associates with integrins has been implicated in the promotion of a migratory cell phenotype. In order to identify a direct link between PKC and integrins in renal cell carcinoma (RCC) the influence of PKC isoforms on integrin expression and possible consequences on proliferation and cell migration was analyzed in RCC cells. The constitutive expression of the PKC isoforms alpha, betaI, betaII, gamma, delta, epsilon, eta, theta, xi, lambda and micro was determined in the RCC cell line CCF-RC1. In addition, the influence of PKC inhibitors RO31-8220, GF109203X and GO6976 on the beta1, beta2 and beta3 integrin expression and cell proliferation of RCC cells was investigated by flow cytometry and by BrdU incorporation, respectively. Furthermore, the motility of CCF-RC1 cells was assessed through chamber chemotaxis analysis. All PKC isoforms tested were expressed in CCF-RC1 cells with the exception of PKClambda and theta. The PKC inhibitor RO31-8220 reduced beta1 integrin expression by 92% and inhibited proliferation by 42% of untreated cells, whereas cell migration remained uninfluenced by RO31-8220. GF109203X and GO6976 reduced beta1 integrin expression to approximately 50% of untreated cells. In contrast, beta2 and beta3 integrins were only weakly affected by RO31-8220, GF109203X and GO6976 treatment. The most significant influence on beta1 integrin expression was obtained by the PKC inhibitor RO31-8220. This leads to the assumption that PKCepsilon is involved in the regulation of beta1 integrin expression. Downregulation of beta1 integrins by RO31-8220 was associated with reduced proliferation, but did not influence migration. These findings provide a conceptual basis for treatment of renal cell carcinoma by interfering with tumor cell proliferation.

Li SY, Yu B, An P, et al.
Effects of cell membrane phospholipid level and protein kinase C isoenzyme expression on hepatic metastasis of colorectal carcinoma.
Hepatobiliary Pancreat Dis Int. 2004; 3(3):411-6 [PubMed] Related Publications
BACKGROUND: The molecular mechanism of hepatic metastasis of colorectal cancer is not well understood. The aim of this study was to assess the relations between phospholipid contents of cellular membrane and isoenzyme expression of protein kinase C (PKC) and their effects on hepatic metastasis of colorectal cancer.
METHODS: High performance liquid chromatography was used to detect contents of cell membrane phospholipids: phosphatidylinosital (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in primary foci, paratumor mucosa and hepatic metastatic foci in patients with colorectal carcinoma. The mRNA expression levels of PKC-alpha, -betaII, -delta, -epsilon, -lambda, -zeta isoenzymes were detected with the QRT-PCR technique.
RESULTS: The levels of PI, PC and PE in primary foci and hepatic metastatic foci were higher than those in paratumor mucosa. The level of PE in hepatic metastatic foci was much higher than that in primary foci (t=98.88, P<0.01); but the levels of PI and PC were not significantly different between primary foci and hepatic metastatic foci (t=1.73, 1.36, P>0.05). The expression levels of PKC-betaII, -delta, -epsilon, -lambda, -zeta were enhanced in primary foci and hepatic metastatic foci, but the level of PKC-alpha in primary foci was decreased as compared with that in paratumor mucosa. The levels of PKC-delta, -epsilon, -lambda, -zeta in hepatic metastatic foci were higher than those in primary foci. A positive correlation was observed between the expression levels of PI, PC and PKC-betaII and also between those of PE and PKC-delta, -epsilon, -lambda, -zeta. However, there was a close negative correlation between PE and PKC-alpha.
CONCLUSION: Increased levels of PI and PC and decreased ratio of PKC-alpha to PKC-betaII are related to colorectal cancer genesis. Increased levels of PE, increased expression of PKC-delta, -epsilon, -lambda, -zeta isoenzymes and decreased level of PKC-alpha are related to hepatic metastasis in colorectal carcinoma.

Chu F, Chen LH, O'Brian CA
Cellular protein kinase C isozyme regulation by exogenously delivered physiological disulfides--implications of oxidative protein kinase C regulation to cancer prevention.
Carcinogenesis. 2004; 25(4):585-96 [PubMed] Related Publications
We reported previously that cystine produces regulatory responses in purified, recombinant human protein kinase C-delta (PKCdelta) and PKCepsilon via S-thiolation-triggered mechanisms that are consistent with a cancer preventive effect, i.e. stimulation of the pro-apoptotic, tumor-suppressive isozyme PKCdelta and inactivation of the growth-stimulatory, oncogenic isozyme PKCepsilon, at S-cysteinylation stoichiometries that correspond to modification of a single redox-regulatory cysteine (Cys) switch in each isozyme. In this report, we show that the oxidative regulatory responses of purified PKCdelta and PKCepsilon to cystine are recapitulated in disulfide-treated cells. We report that treatment of COS7-PKCepsilon transfectants with the cystine precursor cystine dimethyl ester (CDME) produced concentration- and time-dependent PKCepsilon inactivation that was associated with oxidative PKCepsilon modification manifested as attenuated band intensity in PKCepsilon immunoblot analyses, and that both PKCepsilon inactivation and modification were reversed by dithiothreitol (DTT) as well as by thioredoxin. We also show that CDME induced biphasic PKCdelta regulation in COS7-PKCdelta transfectants, with DTT-irreversible PKCdelta stimulation at low and DTT-reversible PKCdelta inactivation at high CDME concentrations. The degrees of PKCdelta versus PKCepsilon inactivation by CDME treatment of COS7-PKC transfectants indicate substantial resistance of PKCdelta to inactivation. The PKCdelta stimulatory response in COS7-PKCdelta cells was triggered only by the disulfide agent and not by its reduced thiol counterpart, providing evidence for an oxidative mechanism. Also paralleling the oxidative stimulation of purified PKCdelta by cystine, the stimulation of PKCdelta elicited by CDME treatment of cells involved a stable structural change, which was evident from the stability of the stimulated form of PKCdelta to immunoprecipitation. Demonstration of oxidative regulation of cellular PKCdelta and PKCepsilon by disulfides in this report provides evidence that redox-regulatory sites in PKCdelta and PKCepsilon may offer novel targets for development of cancer preventive or therapeutic agents that selectively inactivate PKCepsilon or stimulate PKCdelta.

Schultz A, Jönsson JI, Larsson C
The regulatory domain of protein kinase Ctheta localises to the Golgi complex and induces apoptosis in neuroblastoma and Jurkat cells.
Cell Death Differ. 2003; 10(6):662-75 [PubMed] Related Publications
This study investigates apoptotic effects of protein kinase C (PKC) delta and theta in neuroblastoma cells. 12-O-tetradecanoylphorbol-13-acetate induces apoptosis in SK-N-BE(2) neuroblastoma cells overexpressing PKCdelta or PKCtheta, but not PKC epsilon. The PKC inhibitor GF109203X does not suppress this apoptotic effect, suggesting that it is independent of the catalytic activity of PKC. The isolated catalytic domains of PKCdelta and PKCtheta or the regulatory domain (RD) of PKCtheta also induce apoptosis in neuroblastoma cells. The apoptotic responses are suppressed by caspase inhibition and by Bcl-2 overexpression. The PKCtheta RD induced apoptosis also in Jurkat cells. Colocalisation analysis revealed that the PKCtheta RD primarily localises to the Golgi complex. The C1b domain is required for this localisation and removal of the C1b domain results in a PKCtheta construct that does not induce apoptosis. This suggests that the PKCtheta RD has apoptotic activity and that Golgi localisation may be important for this effect.

Lindemann RK, Braig M, Ballschmieter P, et al.
Protein kinase Calpha regulates Ets1 transcriptional activity in invasive breast cancer cells.
Int J Oncol. 2003; 22(4):799-805 [PubMed] Related Publications
We have previously shown that PKC inhibitors interfere with the Ets1/Smad3-dependent regulation of parathyroid hormone-related protein (PTHrP) P3 promoter activity by TGFbeta in invasive MDA-MB-231 breast cancer cells. By examining PKC expression in a variety of breast cancer cell lines, the protein level of PKCalpha was found to be much higher in Ets1-expressing MDA-MB-231 and MDA-MB-435 breast cancer cells than in Ets1-deficient MCF-7 and SK-BR3 cells. No correlation of Ets1 expression with the expression of other PKC subtypes (PKCbeta1, PKCbeta2, PKCdelta or PKCepsilon) could be observed. In contrast to MDA-MB-231 cells, PKCalpha-deficient MCF-7 cells do not support Ets1-induced activation of the PTHrP P3 promoter suggesting that PKCalpha may be important for Ets1 activity. A constitutively active form of PKCalpha was found to potentiate the P3 promoter activation by Ets1 alone and in synergy with Smad3. PKCalpha, but not PKCepsilon, also induced phosphorylation of the Ets1 protein. Both PKCalpha effects on Ets1 depended on the exon VII domain of Ets1. Using verapamil and ionomycin, we could show that PKCalpha induces Ets1 phosphorylation independent of calcium mobilization. Collectively, our data suggest that PKCalpha may regulate Ets1 activity in invasive breast cancer cells.

Lindemann RK, Braig M, Hauser CA, et al.
Ets2 and protein kinase C epsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells.
Biochem J. 2003; 372(Pt 3):787-97 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Parathyroid hormone-related protein (PTHrP) promotes the metastatic potential and proliferation of breast cancer cells, and acts anti-apoptotically. In invasive MDA-MB-231 breast cancer cells, transforming growth factor beta-regulated PTHrP synthesis is mediated by an Ets1/Smad3-dependent activation of the PTHrP P3 promoter. In the present study, we studied the regulation of PTHrP expression in non-invasive, Ets1-deficient and transforming growth factor beta-resistant MCF-7 cells. We found PMA to be a strong stimulator of P3-dependent PTHrP expression in MCF-7 cells. Mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase 1 (MEK-1)/ERK1/2 inhibitor PD98059 interfered with this activity. Promoter studies revealed that the PMA effect depended on the Ets and stimulating protein-1 (Sp1)-binding sites. Of several Ets factors tested, Ets2, but not Ese-1, Elf-1 or Ets1, supported the PMA-dependent increase in promoter activity. PD98059 and a threonine to alanine mutation of the ERK1/2-responsive Ets2 phosphorylation site at position 72 inhibited the Ets2/PMA effect. Activated protein kinase C (PKC) epsilon could mimic PMA by stimulating the P3 promoter alone or in co-operation with Ets2 in an MEK-1/ERK1/2-dependent manner. Activated PKC alpha, although capable of co-operating with Ets2, failed to induce transcription from the P3 promoter on its own. The Ets2/PKalpha synergistic effect was neither sensitive to PD98059 nor to Thr(72)/Ala(72) mutation. PMA neither increased the expression of Sp1 nor modulated the transcriptional activity of Sp1. However, it induced the displacement of a yet unknown factor from the Sp1-binding site, which may result in Sp1 recruitment to the promoter. Our results suggest an ERK1/2-dependent Ets2/PKC epsilon synergism to be involved in PTHrP expression in MCF-7 breast cancer cells.

Wu D, Terrian DM
Regulation of caveolin-1 expression and secretion by a protein kinase cepsilon signaling pathway in human prostate cancer cells.
J Biol Chem. 2002; 277(43):40449-55 [PubMed] Related Publications
Caveolin-1, androgen receptor, c-Myc, and protein kinase Cepsilon (PKCepsilon) proteins are overrepresented in most advanced prostate cancer tumors. Previously, we demonstrated that PKCepsilon has the capacity to enhance the expression of both caveolin-1 and c-Myc in cultured prostate cancer cells and is sufficient to induce the growth of androgen-independent tumors. In this study, we have uncovered further evidence of a functional interplay among these proteins in the CWR22 model of human prostate cancer. The results demonstrated that PKCepsilon expression was naturally up-regulated in recurrent CWR22 tumors and that this oncoprotein was required to sustain the androgen-independent proliferation of CWR-R1 cells in culture. Gene transfer experiments demonstrated that PKCepsilon had the potential to augment the expression and secretion of a biologically active caveolin-1 protein that supports the growth of the CWR-R1 cell line. Antisense and pharmacological experiments provided additional evidence that the sequential activation of PKCepsilon, mitogen-activated protein kinases, c-Myc, and androgen receptor signaling drove the downstream expression of caveolin-1 in CWR-R1 cells. Finally, we demonstrate that mitogen-activated protein kinases were required downstream of PKCepsilon to derepress the transcriptional elongation of the c-myc gene. Our findings support the hypothesis that PKCepsilon may advance the recurrence of human prostate cancer by promoting the expression of several important downstream effectors of disease progression.

Ding L, Wang H, Lang W, Xiao L
Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway.
J Biol Chem. 2002; 277(38):35305-13 [PubMed] Related Publications
The serine/threonine protein kinase C (PKC) has been implicated in the regulation of drug resistance and cell survival in many types of cancer cells. However, the one or more precise mechanisms remain elusive. In this study, we have identified and determined the mechanism by which PKC-epsilon, a novel PKC isoform, modulates drug resistance in lung cancer cells. Western blot analysis demonstrates that expression of PKC-epsilon, but not other PKC isoforms, is associated with the chemo-resistant phenotype of non-small cell lung cancer (NSCLC) cell lines. Northern blotting and nuclear run-on transcription analysis further reveals that the failure of expression of PKC-epsilon in the chemo-sensitive phenotype of small cell lung cancer (SCLC) cells results from transcriptional inactivation of the gene. Importantly, forced expression of PKC-epsilon in NCI-H82 human SCLC cells confers a significant resistance to the chemotherapeutic drugs, etoposide and doxorubicin. Resistance is characterized by a significant reduction in apoptosis in PKC-epsilon-expressing cells. Treatment of NCI-H82 cells with etoposide induces a series of time-dependent events, including the release of cytochrome c from the mitochondria to the cytosol, activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). All of these events are blocked by PKC-epsilon expression. Furthermore, caspase-specific inhibitors, z-VAD-fmk and z-DEVD-fmk, significantly attenuate the accumulation of sub-G(1) population and block the PARP cleavage in response to etoposide. These results suggest that PKC-epsilon prevents cells from undergoing apoptosis through inhibition of the mitochondrial-dependent caspase activation, thereby leading to cell survival. Finally, down-regulation of PKC-epsilon expression by the antisense cDNA in NSCLC cells results in increased sensitivity to etoposide. Taken together, our findings suggest an important role for PKC-epsilon in regulating survival of lung cancer cells.

Knauf JA, Ward LS, Nikiforov YE, et al.
Isozyme-specific abnormalities of PKC in thyroid cancer: evidence for post-transcriptional changes in PKC epsilon.
J Clin Endocrinol Metab. 2002; 87(5):2150-9 [PubMed] Related Publications
PKC isozymes are the major binding proteins for tumor-promoting phorbol esters, and PKC activity is abnormal in a number of different human cancers. Less is known about putative structural and functional changes of specific PKC isozymes in human neoplasms. A single-point mutation of PKCalpha at position 881 of the coding sequence has been observed in human pituitary adenomas and up to 50% of thyroid follicular neoplasms, and a rearrangement of PKCepsilon was reported in a thyroid follicular carcinoma cell line, suggesting that these signaling proteins may play a role in thyroid tumorigenesis. To explore this possibility, we examined thyroid neoplasms for mutations and changes in expression levels of PKCepsilon or alpha. None of the 57 follicular adenomas, 26 papillary carcinomas (PCs), 7 follicular carcinomas, or the anaplastic carcinoma harbored the PKCalpha 881A>G mutation. Moreover, none of 15 PCs, 10 follicular adenomas, or 6 follicular carcinomas showed evidence of mutations of PKCepsilon. However, 8 of 11 PCs had major isozyme-specific reductions of the PKCepsilon protein, which occurred through either translational or posttranslational mechanisms. These data indicate that post-transcriptional changes in PKCepsilon are highly prevalent in thyroid tumors and may play a significant role in their development.

Wu D, Foreman TL, Gregory CW, et al.
Protein kinase cepsilon has the potential to advance the recurrence of human prostate cancer.
Cancer Res. 2002; 62(8):2423-9 [PubMed] Related Publications
Prostatic epithelial cells that are capable of surviving in the absence of androgenic steroids were found to express protein kinase Cepsilon (PKCepsilon), an oncogenic protein capable of promoting autocrine cell-signaling events. Gene transfer experiments demonstrated that PKCepsilon overexpression was sufficient to transform androgen-dependent LNCaP cells into an androgen-independent variant that rapidly initiated tumor growth in vivo in both intact and castrated male nude mice. This transformation was associated with an accelerated rate of androgen-independent LNCaP cell proliferation, resistance to apoptosis, hyperphosphorylation of the mitogen-activated protein kinase extracellular signal-regulated kinase and transcriptional repressor protein retinoblastoma, and increased expression of E2F-1 and other 5'-cap-dependent mRNAs, including the G(1) cyclins, c-myc, and caveolin-1. Coimmunoprecipitation experiments indicated that PKCepsilon was associated with members of the extracellular signal-regulated kinase signaling cascade and the scaffolding protein caveolin-1. Caveolin-1, produced by LNCaP cells overexpressing PKCepsilon, was released into the medium, possibly through a Golgi-independent route, and significant growth inhibition was observed when these cells were cultured in the presence of an anti-caveolin-1 antiserum. Finally, antisense experiments established that endogenous PKCepsilon plays an important role in regulating the growth and survival of androgen-independent prostate cancer cells. This study provides several independent lines of evidence supporting the hypothesis that PKCepsilon expression may be sufficient to maintain prostate cancer growth and survival after androgen ablation.

Song MS, Park YK, Lee JH, Park K
Induction of glucose-regulated protein 78 by chronic hypoxia in human gastric tumor cells through a protein kinase C-epsilon/ERK/AP-1 signaling cascade.
Cancer Res. 2001; 61(22):8322-30 [PubMed] Related Publications
The M(r) 78,000 glucose-regulated protein (GRP78) can be induced by physiological stresses such as glucose deprivation and hypoxia. In solid tumors, hypoxia can promote malignant progression and confer resistance to irradiation and chemotherapy by altering gene expression. Here, we investigated the molecular mechanisms and signaling pathway involved in the late and prolonged induction of the GRP78 gene by hypoxia in a human gastric cancer cell line, MKN28. Nuclear run-on assays and mRNA stability measurements revealed that transcriptional activation, not stabilization of mRNA, contributed to the dramatic induction of GRP78 gene under hypoxia. Induction of GRP78 by chronic hypoxia was completely abolished by pretreatment with PD98059 [a specific inhibitor of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK1)] or by overexpression of a dominant-negative MEK1 mutant, demonstrating a direct involvement of ERK in the induction of transcription at the GRP78 promoter under these conditions. Furthermore, hypoxia increased the transcriptional activity of a 12-O-tetradecanoylphorbol-13-acetate response element-like motif on the GRP78 promoter and increased the abundance and DNA binding activity of AP-1 complex composed of c-Jun and c-Fos. A selective protein kinase C (PKC) inhibitor, GF109203X, inhibited the induction of GRP78 gene expression as well as the activities of both ERK and Raf-1. Among six PKC isoforms expressed in MKN28 cells, PKC-epsilon expression level and kinase activity were increased by hypoxia. Transfection of MKN28 cells with a dominant-negative PKC-epsilon blocked the induction of GRP78 through ERK by hypoxia, indicating that PKC-epsilon directly participated in GRP78 induction under hypoxia. Taken together, this study shows that a PKC-epsilon-Raf-1-MEK-ERK-AP1 signaling cascade acts on a 12-O-tetradecanoylphorbol-13-acetate response element-like element to mediate hypoxia-induced GRP78 expression in human gastric cancer cells. We also confirmed in vivo the overexpression of GRP78 in surgical specimens of human primary gastric tumors.

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