Protein Kinase C Has the Potential to Advance the Recurrence of Human Prostate Cancer1 (original) (raw)
Related papers
Biochemical and Biophysical Research Communications, 1998
AR gene , other cellular pathways may be involved. The protein kinase C (PKC) activator 12-O-tetrade-Growth factors that are recognized to have an imcanoyl-phorbol-13-acetate (TPA) activated cell death portant role in prostatic tumor biology (2, 7, 8) signal in androgen-sensitive LNCaP cells but not in androthrough protein kinase C (PKC) (9-11) to elicits a plethgen-independent DU-145 or PC-3 cells, whose growth ora of cellular responses on cell growth and differentiawas significantly decreased by PKC inhibitors staurotion (12, 13). Furthermore, androgenic regulation of sporine and H7. All cell lines had similar levels of total prostatic genes, including the androgen receptor, is dis-PKC activities which, however, differed on their derupted when cells are treated with protein kinase C pendency on Ca 2/ ions and lipid and were regulated activators (14). Here we show that the PKC activator differently by TPA. Furthermore, expression of the im-TPA elicits disparate responses in androgen-sensitive mediate early genes c-fos and c-jun was up-regulated and insensitive prostatic cancer cells suggesting that by TPA only in LNCaP and DU-145 cells, whereas PCalterations in PKC-isozymes may contribute to andro-3 cells failed to express c-fos mRNA. The regulation gen insensitivity in prostatic cancer. of the c-myc mRNA by TPA correlated inversely with activation of cell death being down-regulated in LNCaP cells, and slightly increased in the androgen-MATERIALS AND METHODS independent cell lines. These results suggest that the PKC signal transduction pathway functions differ-Probes. The glyceraldehyde-3-phosphate dehydrogenase (GADPH) 2 Corresponding
Transgenic overexpression of pkcε in the mouse prostate induces preneoplastic lesions
Cell Cycle, 2011
It is well established that protein kinase C (PKC) isozymes play distinctive roles in mitogenic and survival signaling as well as in cancer progression. PKCε, the product of the PRKCE gene, is upregulated in various types of cancers including prostate, lung and breast cancer. To address a potential role for PKCs in prostate cancer progression we generated three mouse transgenic lines expressing PKCα, PKCδ or PKCε in the prostate epithelium under the control of the rat probasin (PB) promoter. Whereas PB-PKCα and PB-PKCδ mice did not show any evident phenotype, PB-PKCε mice developed prostate hyperplasia as well as prostate intraepithelial neoplasia (PIN) that displayed enhanced phospho-Akt, phospho-S6 and phospho-Stat3 levels, as well as enhanced resistance to apoptotic stimuli. PKCε overexpression was insufficient to drive neoplastic changes in the mouse prostate. Notably, overexpression of PKCε by adenoviral means in normal immortalized RWPE-1 prostate cells confers a growth advantage and hyperactivation of Erk and Akt. Our results argue for a causal link between PKCε overexpression and prostate cancer development.
Protein Kinase C Epsilon Overexpression in Prostate Adenocarcinoma is Associated with Oncogenesis
Journal of Advanced Zoology
Background: PKCε, an isozyme of serine-threonine kinase, has been implicated in epithelial cancer metastasis and progression. This study investigates the impact of the oncogenic PKCε, overexpressed abnormally in human Prostate tumor samples and cell lines, to understand its efficacy. Methods: The microarray dataset, GSE86257, was processed for normalization. The identification of upregulated and downregulated genes was based on FDR >1 and p <0.05 values. Cytoscape analysis and functional enrichment of significant genes were done. The identified genes were validated on the TCGA dataset and survival analysis was performed by Kaplan-Meier analysis. Results: A total of 1524 DEGs were identified with 728 upregulated genes and 818 downregulated genes. The two significant modules with MCODE score:9.0 and Venn analysis provided cyclin-dependent kinase inhibitor protein (CDK1), Cyclin B1 (CCNB1), Phospholipase C Gamma 1 (PLCG1), Cyclin Dependent Kinase 9 (CDK9), Phosphoinositide-3-Kina...
Protein Kinase C Isoenzyme Patterns Characteristically Modulated in Early Prostate Cancer
The American Journal of Pathology, 1999
and -, and of their common receptor for activated C-kinase (RACK)-1 , was determined immunohistochemically using specific antibodies in formalin-fixed and paraffin-embedded specimens of early prostatic adenocarcinomas (n ؍ 23) obtained at radical prostatectomy. Expression of each isoenzyme by malignant tissues was compared with nonneoplastic prostate tissues removed at radical cystectomy (n ؍ 10). The most significant findings were decreased PKC- expression in early neoplasia when compared to benign epithelium (P < 0.0001), together with a reciprocal increase in expression of PKC-⑀ (P < 0.0001). Detectable levels of PKC-␣ and PKC-were also significantly increased in the cancers (P ؍ 0.045 and P ؍ 0.015 respectively) but did not correlate with either PKC- or PKC-⑀ for individual cases. Alterations in the levels of the four PKC isoenzymes occurred specifically and consistently during the genesis and progression of human prostate cancer. PKC-␦, -␥, and -were not expressed in the epithelium of either the benign prostates or the cancers. Levels of expression for PKC-, -, -, and RACK-1 were not significantly different between the benign and malignant groups. Although changes in PKC isoenzyme expression may assist in explaining an altered balance between proliferation and apoptosis, it is likely that changes in activity or concentrations of these isoenzymes exert important modulating influences on particular pathways regulating cellular homeostasis. The findings of this study raise an exciting possibility of novel therapeutic intervention to regulate homeostatic mechanisms controlling proliferation and/or apoptosis , including expression of the p170 drug-resistance glycoprotein , intracellular Ca 2؉ concentrations , and enhanced cellular mobility resulting in the metastatic dissemination of human prostate cancer cells. Attenuation of PKC- expres-sion is currently being assessed as a reliable objective adjunct to morphological appearance for the diagnosis of early progressive neoplasia in human prostatic tissues.
Differential regulation of prostatic protein kinase C isozymes by androgens
FEBS Letters, 1990
Multiple isozymes of Ca2+/phospholipid‐dependent protein kinase (PKC) were isolated from the rat ventral prostate. The enzyme exists mainly as type II (β), and type III (α) forms, and it is possible that type II isozyme may comprise the subspecies β1 and β2. The total and specific activities of prostatic PKC isoforms were reduced in castrated animals; this decrease was specific since administration of androgens to castrated animals reversed such a decline. Also, there was a differential response to androgen deprivation so that type III isozyme declined at a faster rate than that of type II. Thus, our studies show for the first time that PKC of the rat ventral prostate comprises multiple isozymes, and that the activity of these various forms are differentially regulated by androgens.
Endocrine Related Cancer, 2005
In a previous report, we showed that increased activation of Akt, a downstream effector of phosphoinositide 3-kinase (PI3K) together with decreased activation of extracellular-signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) family, predicted poor clinical outcome in prostate cancer (Kreisberg et al. 2004 Cancer Research 64 5232-5236). We now show that Akt activation, but not ERK activation, is correlated with proliferation in human prostate tumors as estimated by the expression of the cell proliferation antigen Ki67. We verified these results in vitro, using the androgen-dependent prostate cancer cell line LNCaP and its androgen-independent clone C4-2 as models of prostate cancer of good and poor clinical outcome, respectively. C4-2 cells expressed higher Akt activation, lower ERK activation and increased proliferation compared with LNCaP cells, similar to cases of poor clinical outcome. The PI3K inhibitor LY294002, but not the MAPK/ERK kinase inhibitor PD98059, induced growth arrest in both cell lines. Transient transfection with constitutively active Akt increased proliferation while dominant negative Akt decreased it, thus showing that Akt plays an important role in prostate cancer proliferation. Akt regulates the expression and activation of the androgen receptor. Androgen receptor inhibition with Casodex induced growth arrest in LNCaP cells, but not in C4-2 cells. Another PI3K downstream effector, p70 S6 kinase, requires prior phosphorylation by mammalian target of rapamycin (mTOR) for complete activation. Activation of p70 S6 kinase was higher in C4-2 compared with LNCaP cells. Rapamycin, an mTOR inhibitor, had a growth-inhibitory effect in C4-2 cells, but not in LNCaP cells. Our data suggest a shift from a Casodex-sensitive proliferation pathway in LNCaP cells to a rapamycinsensitive pathway in C4-2 cells.
FEBS open bio, 2018
Prostate cancer is one of the most common cancers in men. Although it has a relatively high 5-year survival rate, development of resistance to standard androgen-deprivation therapy is a significant clinical problem. Therefore, novel therapeutic strategies are urgently needed. The protein kinase C (PKC) family is a putative prostate cancer drug target, but so far no PKC-targeting drugs are available for clinical use. By contrast to the standard approach of developing PKC inhibitors, we have developed isophthalate derivatives as PKC agonists. In this study, we have characterized the effects of the most potent isophthalate, 5-(hydroxymethyl)isophthalate 1a3 (HMI-1a3), on three prostate cancer cell lines (LNCaP, DU145, and PC3) using both 2D and 3D cell culture models. In 2D cell culture, HMI-1a3 reduced cell viability or proliferation in all cell lines as determined by the metabolic activity of the cells (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay) and thymidin...
Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells
Oncogene, 2006
Progression of prostate cancer to androgen independence is suspected to involve the androgen and protein kinase A (PKA) signaling pathways. Here for the first time, the transcriptomes associated with each pathway and common transcriptional targets in response to stimulation of both pathways were identified in human prostate cancer cells using Affymetrix GeneChip technology (Human Genome U133 plus2). Statistically significant changes in the levels of 858 genes in response to androgen and 303 genes in response to activation of the PKA pathway were determined using GeneSpring software. Expression of a subset of these genes (22) that were transcriptional targets for the androgen and/or PKA pathways were validated by reverse transcriptase-polymerase chain reaction and Western blot analyses. Application of small interfering RNAs to the androgen receptor (AR) revealed that in addition to KLK3, levels of expression of KLK2 and SESN1 were regulated by AR activated by both the androgen and PKA signaling pathways. SESN1 was identified as a gene repressed by activated AR. These results provide a broad view of the effects of the androgen and PKA signaling pathways on the transcriptional program of prostate cancer cells and indicate that only a limited number of genes are targeted by cross-talk between AR and PKA pathways.
Cancer Research, 2011
Protein kinase C epsilon (PKCε), a novel PKC isoform is over-expressed in prostate cancer (PCa) and correlates with disease aggressiveness. However, the functional contribution of PKCε to development or progression of PCa remained to be determined. Here we present the first in vivo genetic evidence that PKCε is essential for both the development and metastasis of PCa in the transgenic mouse model of prostate adenocarcinoma (TRAMP). Heterozygous or homozygous genetic deletions of PKCε in FVB/N TRAMP inhibited on PCa development and metastasis as analyzed by CT-PET scanning, tumor weight determinations and histopathology. We also examined biomarkers associated with tumor progression in this model, including markers of survival, proliferation, angiogenesis, inflammation, and metastatic progression. To find clues about the genes regulated by PKCε and linked to the Stat3 signaling pathway, we performed focused PCR arrays of JAK/STAT signaling in excised PCa tissues from PKCε wild type and nullizygous TRAMP mice. Notably, PKCε loss was associated with significant down-regulation in tumors of proliferative and metastatic genes C/EBP-β, C-reactive protein, CMK, EGFR, CD64, JunB, and gp130. Taken together, our findings offer first genetic evidence of the link of PKCε in PCa development and metastasis. PKCε may be potential target for prevention and/or treatment of PCa.
Carcinogenesis, 2002
Because of the heterogeneous nature of prostate cancer, identifying the molecular mechanisms involved during the transition from an androgen-sensitive to an androgenindependent phenotype is very complex. An LNCaP cell model that recapitulates prostate cancer progression, comprising early passage androgen-sensitive (LNCaP-C33) and late passage androgen-independent (LNCaP-C81) phenotypes, would help to provide a better understanding of such molecular events. In this study, we examined the genes expressed by LNCaP-C33 and LNCaP-C81 cells using cDNA microarrays containing 1176 known genes. This analysis demonstrated that 34 genes are up-regulated and eight genes are down-regulated in androgen-independent cells. Northern blot analysis confirmed the differences identified by microarrays on several candidate genes, including c-MYC, c-MYC purine-binding transcription factor (PuF), macrophage migration inhibitory factor (MIF), macrophage inhibitory cytokine-1 (MIC-1), lactate dehydrogenase-A (LDH-A), guanine nucleotide-binding protein Gi, α-1 subunit (NBP), cyclin dependent kinase-2 (CDK-2), prostate-specific membrane antigen (PSM), cyclin H (CCNH), 60S ribosomal protein L10 (RPL10), 60S ribosomal protein L32 (RPL32), and 40S ribosomal protein S16 (RPS16). These differentially-regulated genes are correlated with progression of human prostate cancer and may be of therapeutic relevance as well as an aid in understanding the molecular genetic events involved in the development of this disease's hormone-refractory behavior.