Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we described that bone morphogenetic protein-7 (BMP7) could protect prostate cancer C4-2B cells from serum starvation-induced apoptosis via survivin induction. Here, for the first time, we identify Runx2 as a key regulator of survivin transcription. In C4-2B cells grown normally, suppression of Runx2 reduced survivin expression. Using ChIP assays, two regions of the survivin promoter, -1953 to -1812 (I) and -1485 to -1119 (II) encompassing consensus Runx-binding sites were examined. Runx2 was found to be associated with both regions, with a stronger affinity to region-I. In serum-starved cells neither region was occupied, but BMP7 restored association to region-II and not region-I. In reporter assays, transcription activity by BMP7 was significantly reduced when sequences including binding sites of region-II were deleted. Additionally, Runx2 expression was enhanced by BMP7 in these cells. Along with a strong survivin expression, a trend in increased Runx2 expression in human prostate cancer cells and tissues was noted. In the conditional Pten-knockout mouse, Runx2 level increased with growth of prostate tumor. The data define a novel role of Runx2 in regulating survivin expression in malignant epithelial cells and identify it as a critical factor in BMP signaling that protects cancer cells against apoptosis.
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PMID:Runx2 regulates survivin expression in prostate cancer cells. 1994 74

CCL2 is a cytokine prevalent in the prostate cancer tumor microenvironment. Recently, we reported that CCL2 induces the mammalian target of rapamycin (mTOR) pathway to promote prostate cancer PC3 cell survival; however, the mechanism used by CCL2 to maintain mTOR complex-1 (mTORC1) activation requires clarification. This study demonstrates that upon serum starvation, CCL2 functions as a negative regulator of AMP-activated protein kinase (AMPK) by decreasing phosphorylation at its major regulatory site (Thr(172)) in PC3, DU145, and C4-2B prostate cancer cells. The CCL2-mediated AMPK regulation decreased raptor phosphorylation (Ser(792)) resulting in hyperactivation of mTORC1. D942, a pharmacological activator of AMPK, stunted CCL2-induced mTORC1 activity, survivin expression, and cell survival without significantly affecting Akt activity. CCL2, however, conferred some resistance to the lethal effect of D942 compared with untreated cells. By using Akt-specific inhibitor X, it was shown that Akt inactivation did not cause an increase in AMPK phosphorylation in CCL2-stimulated cells, suggesting that CCL2-mediated negative regulation of AMPK is independent of Akt. Furthermore, bisindolylmaleimide-V, a specific inhibitor of p70(S6K), stunted survivin expression and induced cell death in CCL2-treated PC3. Altogether, these findings suggest that CCL2 hyperactivates mTORC1 through simultaneous regulation of both AMPK and Akt pathways and reveals a new network that promotes prostate cancer: CCL2-AMPK-mTORC1-survivin.
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PMID:CCL2 is a negative regulator of AMP-activated protein kinase to sustain mTOR complex-1 activation, survivin expression, and cell survival in human prostate cancer PC3 cells. 2001 39

Glycogen synthase kinase 3 beta (GSK-3beta) is constantly active in cells and its activity increases after serum deprivation, indicating that GSK-3beta might play a major role in cell survival under serum starvation. In this study, we attempted to determine how GSK-3beta promotes cell survival after serum depletion. Under full culture conditions (10% FBS), GSK-3beta inhibition with chemical inhibitors or siRNAs failed to induce cell death in human prostate cancer cells. By contrast, under conditions of serum starvation, a profound necrotic cell death was observed as evidenced by cellular morphologic features and biochemical markers. Further analysis revealed that GSK-3beta-inhibition-induced cell death was in parallel with an extensive autophagic response. Interestingly, blocking the autophagic response switched GSK-3beta-inhibition-induced necrosis to apoptotic cell death. Finally, GSK-3beta inhibition resulted in a remarkable elevation of Bif-1 protein levels, and silencing Bif-1 expression abrogated GSK-3beta-inhibition-induced autophagic response and cell death. Taken together, our study suggests that GSK-3beta promotes cell survival by modulating Bif-1-dependent autophagic response and cell death.
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PMID:GSK-3beta promotes cell survival by modulating Bif-1-dependent autophagy and cell death. 2015 67

Prostate stromal cells may play binary roles in the process of prostate cancer development. As the first to be encountered by infiltrating prostate cancer cells, prostate stromal cells form the first defense line against prostate cancer progression and metastasis. However, interaction between prostate cancer and stromal cells may facilitate the formation of a tumor microenvironment favoring cancer cell growth and survival. To establish an experimental system for studying the interaction between cancer and stromal cells, we isolated three matched pairs of normal and cancer-associated human prostate stromal clones. In this report, we describe the morphologic and behavioral characteristics of these cells and their effect on LNCaP prostate cancer cells in co-culture. Unlike LNCaP prostate cancer cells, the isolated prostate stromal clones are large fibroblast-like cells with a slow proliferation rate. Growth and survival of these clones are not affected by androgens. The stromal cells display high resistance to serum starvation, while cancer-associated stromal clones have differentiated survival ability. In co-culture experiments, the stromal cells protected some LNCaP prostate cancer cells from death by serum starvation, and cancer-associated stromal clones showed more protection. This work thus established a panel of valuable human prostate stromal cell lines, which could be used in co-culture to study the interaction between prostate cancer and prostate stromal cells.
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PMID:Matched pairs of human prostate stromal cells display differential tropic effects on LNCaP prostate cancer cells. 2038 66

Deregulation of cyclin expression has been found in many tumors. In this report, we studied expression of cyclin DI in three human prostate cancer cell lines: the androgen-dependent LNCaP and the androgen-independent PC3 and DU 145 cell lines. Northern blot analysis showed that DU145 and PC3 cells expressed more abundant cyclin DI than LNCaP cells. Southern blot analysis showed no evident gene amplification or rearrangement of cyclin DI in any of these cell lines. Serum starvation and replenishment were used in the cell culture to study the regulation of expression of cyclin DI. Cyclin DI mRNA expression was detected by Northern blot analysis when LNCaP cells grew in medium with serum but was not detected after serum withdrawal; however, cyclin DI mRNA was induced after serum was added. Cyclin DI mRNA expression by PC3 and DU 145 cells was detected both when they grew in medium with serum and after serum withdrawal, although expression decreased greatly after 24 hours in the PC3 cell line. Immunoprecipitation and immunohistochemical staining also showed that cyclin D I protein was always expressed in PC3 and DU 145 cells under different growth factor environment, whereas it decreased significantly in LNCaP cells deprived of serum and the level resumed again when serum was re-added. This suggests that expression of cyclin DI is regulated by exogenous growth factors in LNCaP cell line and becomes constitutive in PC3 and DU 145 cell lines.
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PMID:Expression of cyclin DI in human prostate cancer cell lines. 2122 1

The varied reactions of the host to infection, inflammation, or trauma are collectively known as the acute-phase response and encompass a wide range of pathophysiological responses such as pyrexia, leukocytosis, hormone alterations, and muscle protein depletion combining to minimize tissue damage while enhancing the repair process. The mechanism for stimulation of hepatic production of acute-phase proteins is by proinflammatory cytokines. The functions of positive acute-phase proteins (APP) are regarded as important in optimization and trapping of microorganism and their products, in activating the complement system, in binding cellular remnants like nuclear fractions, in neutralizing enzymes, scavenging free hemoglobin and radicals, and in modulating the host's immune response. APP can be used as diagnostic tool in many diseases like bovine respiratory syncytial virus, prostate cancer, bronchopneumonia, multiple myeloma, mastitis, Streptococcus suis infection, starvation, or lymphatic neoplasia. Thus, acute-phase proteins may provide an alternative means of monitoring animal health.
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PMID:Acute-phase proteins: As diagnostic tool. 2143 Sep 62

Increasing evidence suggests that bone marrow derived mesenchymal stem cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis, or by inducing anticancer-drug resistance. Prostate cancer cells secrete ligands of epidermal growth factor receptor (EGFR) and EGFR signaling could play an important role in the cross-talk between mesenchymal stem cells and prostate cancer cells. In this study, we showed that treatment of human primary MSCs with conditioned medium (CM) derived from the bone metastatic PC3 carcinoma cells (PC3-CM) resulted in: a significant activation of EGFR; increased proliferation; increased osteoblastic but decreased adipocitic differentiation; inhibition of senescence induced by serum starvation; increased CCL5 secretion. These activities were significantly inhibited in the presence of the EGFR tyrosine kinase inhibitor gefitinib. PC3-CM directly inhibited osteoclastogenesis as well as the ability of osteoblasts to induce osteoclast differentiation. The increased MSCs migration by PC3-CM and PC3 cells was partially mediated by CCL5. MSC-CM increased the formation of colonies by PC3 cells and inhibited the anti-proliferative activity of Docetaxel. Activation of EGFR expressed on MSCs by PC3-CM enhanced their capability to increase PC3 cells proliferation and to inhibit Docetaxel activity. These findings, by showing that the tumor-promoting interactions between PC3 cells and MSCs are mediated, at least in part, by EGFR, suggest a novel application of the EGFR-tyrosine kinase inhibitors in the treatment of prostate cancer.
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PMID:Gefitinib inhibits the cross-talk between mesenchymal stem cells and prostate cancer cells leading to tumor cell proliferation and inhibition of docetaxel activity. 2319 62

Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent.
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PMID:Suppression of prostate epithelial proliferation and intraprostatic progrowth signaling in transgenic mice by a new energy restriction-mimetic agent. 2327 6

Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM) 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA) significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4) expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1), which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.
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PMID:In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression. 2334 5

Prostate cancer is the leading form of malignancies among men in the U.S. While surgery carries a significant risk of impotence and incontinence, traditional chemotherapeutic approaches have been largely unsuccessful. Hormone therapy is effective at early stage, but often fails with the eventual development of hormone-refractory tumors. We have been interested in developing therapeutics targeting specific metabolic deficiency of tumor cells. We recently showed that prostate tumor cells specifically lack an enzyme (argininosuccinate synthase, or ASS) involved in the synthesis of the amino acid arginine(1). This condition causes the tumor cells to become dependent on exogenous arginine, and they undergo metabolic stress when free arginine is depleted by arginine deiminase (ADI)(1,10). Indeed, we have shown that human prostate cancer cells CWR22Rv1 are effectively killed by ADI with caspase-independent apoptosis and aggressive autophagy (or macroautophagy)(1,2,3). Autophagy is an evolutionarily-conserved process that allows cells to metabolize unwanted proteins by lysosomal breakdown during nutritional starvation(4,5). Although the essential components of this pathway are well-characterized(6,7,8,9), many aspects of the molecular mechanism are still unclear - in particular, what is the role of autophagy in the death-response of prostate cancer cells after ADI treatment? In order to address this question, we required an experimental method to measure the level and extent of autophagic response in cells - and since there are no known molecular markers that can accurately track this process, we chose to develop an imaging-based approach, using quantitative 3D fluorescence microscopy(11,12). Using CWR22Rv1 cells specifically-labeled with fluorescent probes for autophagosomes and lysosomes, we show that 3D image stacks acquired with either widefield deconvolution microscopy (and later, with super-resolution, structured-illumination microscopy) can clearly capture the early stages of autophagy induction. With commercially available digital image analysis applications, we can readily obtain statistical information about autophagosome and lysosome number, size, distribution, and degree of colocalization from any imaged cell. This information allows us to precisely track the progress of autophagy in living cells and enables our continued investigation into the role of autophagy in cancer chemotherapy.
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PMID:Quantitative analysis of autophagy using advanced 3D fluorescence microscopy. 2366 32


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