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)

Elevated endogenous JNK activity and resistance to Fas receptor-mediated apoptosis have recently been implicated in progression of prostate cancer and can promote resistance to apoptosis in response to chemotherapeutic drugs. In addition, JNK has been demonstrated to promote transformation of epithelial cells by increasing both proliferation and survival. Although numerous studies have reported a role for JNK in promoting Fas receptor-mediated apoptosis, there is a paucity in the literature studying the antiapoptotic function of JNK during Fas receptor-mediated apoptosis. Consequently, we have used the recently described specific JNK inhibitor SP600125 and RNA interference to inhibit endogenous JNK activity in the prostate carcinoma cell line DU 145. We demonstrated that endogenous JNK activity increased the expression of a kinase, HIPK3, that has previously been implicated in multidrug resistance in a number of tumors. HIPK3 has also been reported to phosphorylate FADD. The interaction between FADD and caspase-8 was inhibited, but abrogation of JNK activity or HIPK3 expression was found to restore this interaction and increased the sensitivity of DU 145 cells to Fas receptor-mediated apoptosis. In conclusion, we present novel evidence that JNK regulates the expression of HIPK3 in prostate cancer cells, and this contributes to increased resistance to Fas receptor-mediated apoptosis by reducing the interaction between FADD and caspase-8.
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PMID:JNK regulates HIPK3 expression and promotes resistance to Fas-mediated apoptosis in DU 145 prostate carcinoma cells. 1476 60

Previously, we showed that sulforaphane (SFN), a naturally occurring cancer chemopreventive agent, effectively inhibits proliferation of PC-3 human prostate cancer cells by causing caspase-9- and caspase-8-mediated apoptosis. Here, we demonstrate that SFN treatment causes an irreversible arrest in the G(2)/M phase of the cell cycle. Cell cycle arrest induced by SFN was associated with a significant decrease in protein levels of cyclin B1, cell division cycle (Cdc) 25B, and Cdc25C, leading to accumulation of Tyr-15-phosphorylated (inactive) cyclin-dependent kinase 1. The SFN-induced decline in Cdc25C protein level was blocked in the presence of proteasome inhibitor lactacystin, but lactacystin did not confer protection against cell cycle arrest. Interestingly, SFN treatment also resulted in a rapid and sustained phosphorylation of Cdc25C at Ser-216, leading to its translocation from the nucleus to the cytoplasm because of increased binding with 14-3-3beta. Increased Ser-216 phosphorylation of Cdc25C upon treatment with SFN was the result of activation of checkpoint kinase 2 (Chk2), which was associated with Ser-1981 phosphorylation of ataxia telangiectasia-mutated, generation of reactive oxygen species, and Ser-139 phosphorylation of histone H2A.X, a sensitive marker for the presence of DNA double-strand breaks. Transient transfection of PC-3 cells with Chk2-specific small interfering RNA duplexes significantly attenuated SFN-induced G(2)/M arrest. HCT116 human colon cancer-derived Chk2(-/-) cells were significantly more resistant to G(2)/M arrest by SFN compared with the wild type HCT116 cells. These findings indicate that Chk2-mediated phosphorylation of Cdc25C plays a major role in irreversible G(2)/M arrest by SFN. Activation of Chk2 in response to DNA damage is well documented, but the present study is the first published report to link Chk2 activation to cell cycle arrest by an isothiocyanate.
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PMID:Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C. 1507 69

The issue of p53 requirement for the caspase-mediated apoptosis induced by selenium in a cancer chemoprevention or chemotherapy context has not been critically addressed. We and others have shown that selenite induces apoptotic DNA laddering in the p53-mutant DU145 prostate cancer cells and the p53-null HL60 leukemia cells without the cleavage of poly(ADP-ribose) polymerase (PARP; i.e., caspase-independent apoptosis), whereas selenium compounds leading to the formation of methylselenol induce caspase-mediated apoptosis in these cells. Because selenite induces DNA single strand breaks, and because certain types of DNA damage activate p53, we investigated whether the human LNCaP prostate cancer cells, which contain a wild-type p53, execute selenite-induced apoptosis through caspase pathways. The results showed that exposure of LNCaP cells for 24 hours to lower micromolar concentrations of selenite led to DNA laddering, and to the cleavage of PARP and several pro-caspases. In contrast to this apoptosis sensitivity, LNCaP cells were rather resistant to similar concentrations of the methylselenol precursor methylseleninic acid. Selenite treatment led to a significant increase in p53 phosphorylation on Ser-15 (Ser15P). Time course experiments showed that p53 Ser15P occurred several hours before caspase activation and PARP cleavage. The general caspase inhibitor zVADfmk completely blocked PARP cleavage, and significantly decreased DNA laddering, but did not affect p53 Ser15P. An inhibitor for caspase-8 was equally as protective as that for caspase-9 against the selenite-induced apoptosis. Attenuating p53 by a chemical inhibitor pifithrin-alpha decreased the selenite-induced p53 Ser15P and led to concordant reductions of PARP cleavage and apoptosis. In summary, selenite-induced p53 Ser15P appeared to be important for activating the caspase-mediated apoptosis involving both the caspase-8 and the caspase-9 pathways in the LNCaP cells.
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PMID:Selenite-induced p53 Ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells. 1525 49

Recently, survival benefit by chemotherapy using paclitaxel (PTX) and the induction of thymidine phosphorylase (TP) by PTX have been reported in several solid tumors. On the other hand, TP confers antiapoptotic effect on tumor cells through inhibition of caspase-8 activation in vitro. On the basis of these previous observations, we hypothesized that (a) TP can be induced after PTX treatment in human prostate cancer (PC) and (b) blockade of PTX-induced TP expression can enhance the apoptotic processes in human PC cells. PTX was used to find TP expression in all eight hormone-refractory PC cases after chemotherapy; however, cleaved caspase-8 was not expressed after chemotherapy in the six hormone-refractory PC cases with strong TP expression. In PC cell lines (PC-3, DU 145, and LNCaP), TP expression after PTX treatment was clearly up-regulated in a dose-dependent manner. Cell viability of PC cell lines treated with PTX and TP antisense was significantly reduced in a time-dependent and dose-dependent manner compared with the PTX treatment alone. Likewise, apoptotic index of PC cells treated with PTX and TP antisense was significantly increased in comparison with PTX alone. After complete blockade of PTX-induced TP translation by TP antisense transfection, cleaved form of caspase-3 and poly(ADP-ribose) polymerase was increased, and this exaggeration of apoptosis also ran parallel with caspase-8 activation in a PTX dose-dependent manner. However, in PC cell lines treated with TP antisense alone, neither caspase-3 nor poly(ADP-ribose) polymerase was cleaved despite caspase-8 activation. These results indicate that PTX-induced TP up-regulation is associated with decreased caspase-8 activation. This study is the first report showing that blockade of PTX-induced TP expression could exaggerate the processing of apoptosis in PC cells treated with PTX. Our results provide preclinical evidence that TP could be a new molecular target for enhancing the potency of PTX-mediated apoptosis in PC cells.
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PMID:Blockade of paclitaxel-induced thymidine phosphorylase expression can accelerate apoptosis in human prostate cancer cells. 1549 79

In our continuing search to discover bioactive compounds from natural products, we isolated six new clerodane diterpenes, caseamembrins A to F, from Casearia membranacea and examined their antiproliferative activities in human hormone-resistant prostate cancer PC-3 cells. All of these compounds displayed effective antiproliferative activity using sulforhodamine B assays and induced cell apoptosis by a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL)-reaction technique. The data demonstrated that caseamembrin C was the most effective compound among these clerodane diterpenoids. Caseamembrin C induced down-regulation of Bcl-2 and Bcl-xL expression, while up-regulation of proapoptotic protein Mcl-1S (short chain), suggesting that these Bcl-2 family member proteins may play a role on arbitrating the apoptotic cell death. Caseamembrin C also induced the up-regulation of Fas ligand (FasL) expression, cleavage and activation of caspase-8 and caspase-9, Bid cleavage and activation of executor caspase-3. However, z-IETD-FMK (Z-Ile-Glu-Thr-Asp-fluoromethyl ketone, a selective caspase-8 inhibitor) almost completely inhibited caseamembrin C-induced Bid cleavage without any modification of caspase-9 activation, indicating that the extrinsic pathway of FasL/caspase-8/Bid cascade only played a minor role in the apoptotic signaling. Taken together, it is suggested that caseamembrin C-induced apoptosis is predominantly through the activation of intrinsic apoptosis pathways by causing the down-regulation of Bcl-2 and Bcl-xL expression, up-regulation of Mcl-1S protein and activation of caspase-9 and caspase-3.
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PMID:Investigation of extrinsic and intrinsic apoptosis pathways of new clerodane diterpenoids in human prostate cancer PC-3 cells. 1549 90

We have shown previously that sulforaphane (SFN), a constituent of many edible cruciferous vegetables including broccoli, suppresses growth of prostate cancer cells in culture as well as in vivo by causing apoptosis, but the sequence of events leading to cell death is poorly defined. Using PC-3 and DU145 human prostate cancer cells as a model, we now demonstrate, for the first time, that the initial signal for SFN-induced apoptosis is derived from reactive oxygen species (ROS). Exposure of PC-3 cells to growth-suppressive concentrations of SFN resulted in ROS generation, which was accompanied by disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. All these effects were significantly blocked on pretreatment with N-acetylcysteine and overexpression of catalase. The SFN-induced ROS generation was significantly attenuated on pretreatment with mitochondrial respiratory chain complex I inhibitors, including diphenyleneiodonium chloride and rotenone. SFN treatment also caused a rapid and significant depletion of GSH levels. Collectively, these observations indicate that SFN-induced ROS generation is probably mediated by a nonmitochondrial mechanism involving GSH depletion as well as a mitochondrial component. Ectopic expression of Bcl-xL, but not Bcl-2, in PC-3 cells offered significant protection against the cell death caused by SFN. In addition, SFN treatment resulted in an increase in the level of Fas, activation of caspase-8, and cleavage of Bid. Furthermore, SV40-immortalized mouse embryonic fibroblasts (MEFs) derived from Bid knock-out mice displayed significant resistance toward SFN-induced apoptosis compared with wild-type MEFs. In conclusion, the results of the present study indicate that SFN-induced apoptosis in prostate cancer cells is initiated by ROS generation and that both intrinsic and extrinsic caspase cascades contribute to the cell death caused by this highly promising cancer chemopreventive agent.
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PMID:Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species. 1576 12

Methylselenol has been implicated as an active metabolite for the anticancer effect of selenium in part through the induction of cancer cell apoptosis. Since inactivation of the AKT/protein kinase B negative regulator gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) is common in prostate cancer (PCa), we compared PTEN wild-type DU145 PCa cells (low basal AKT activity) with PTEN-mutant LNCaP PCa cells (high basal AKT activity) for their apoptosis responses to the methylselenol precursor methylseleninic acid (MSeA) and sodium selenite, an inorganic salt. Our results show that LNCaP cells withstood approximately 4 times higher doses of MSeA than DU145 cells, although they were slightly more sensitive than the latter to selenite-induced apoptosis. Treatment by MSeA modestly attenuated AKT phosphorylation and increased phospho-ERK1/2 in LNCaP cells. Selenite treatment increased the phosphorylation of p53 Ser15 and both kinases, but the selenite-induced apoptosis was not influenced by chemical inhibitors of either kinase. In contrast, PI3K/AKT inhibitors greatly sensitized LNCaP cells to apoptosis induced by MSeA, accompanied by increased mitochondrial release of cytochrome c and multiple caspase activation without changing p53 Ser15 phosphorylation. The apoptosis was further accentuated by extracellular signal regulated kinases 1 and 2 (ERK1/2) inhibition without further increase in cytochrome c release. The general caspase inhibitor z-VAD-fmk completely blocked MSeA-induced apoptosis when both kinases were inhibited, whereas a caspase-8 inhibitor exerted a greater protection than did a caspase-9 inhibitor. Transfection of DU145 cells with a constitutively active AKT increased their resistance to MSeA-induced apoptosis. In summary, AKT played an important role in regulating apoptosis sensitivity of LNCaP and DU145 cells to MSeA. An MSeA-induced activation of ERK1/2 in LNCaP cells also contributed to resistance to apoptosis. However, these kinases did not significantly regulate caspase-mediated apoptosis induced by selenite in LNCaP cells. These findings support the differential involvement of these protein kinase pathways in regulating apoptosis induction by different forms of selenium.
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PMID:PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. 1584 51

Fluoroquinolones affect the proliferation and apoptotic cell death of several human malignancies. Therefore, we investigated whether new 6-aminoquinolone derivatives, initially synthesized as anti-HIV agents, could affect the proliferation and apoptotic cell death of human prostate cancer cell lines. PC3 and LNCaP cell lines were used as models of androgen-resistant and androgen-responsive prostate cancer, and proliferation of PC3 and LNCaP cells was strongly inhibited by 6-aminoquinolone WM13. Cytotoxicity, which was more pronounced in LNCaP, was accompanied by morphological changes, DNA damage, arrest at the S/G(2)/M phase of the cell cycle, and an increase of the sub-G(1) population. Molecular mechanism underlying WM13-induced cell death involved caspase-8 and -3 and modulation of the expression of apoptotic genes, as well as cleavage of poly-ADP ribose polymerase. Cell death following the treatment of human prostate cancer cell lines with WM13 can be attributed to apoptosis which, depending on the cell line, proceeds through different pathways.
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PMID:Inhibition of cell growth and induction of apoptosis in human prostate cancer cell lines by 6-aminoquinolone WM13. 1587 Sep 30

Andrographolide was extracted and purified from Andrographis panicula using hexane and water partitioning followed by ethyl acetate extraction and chromatography. It showed selective cytotoxicity to prostate cancer PC-3 cells in vitro. The morphological and biochemical changes induced by the extract in carcinoma PC-3 cell death were studied. In andrographolide-treated cells, evidence of apoptosis such as cell shrinkage and surface microvilli loss after 4-hour treatment and chromatin condensation and fragmentation in H&E-stained cells between 4 to 8 hours after treatment were observed. Under electron microscopy, membrane blebbing and apoptotic bodies formation were seen after 8-hour treatment. Using immunocytochemistry staining and cellular caspase-3 activity assay, andrographolide-treated cells showed considerable caspase-3 activation and caspase-8 in PC-3 cells at 4 and 2 hours after treatment, respectively. This suggests andrographolide-induced cell death was achieved through the apoptotic pathway, via the activation of an extrinsic caspase cascade.
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PMID:Morphological and biochemical changes of andrographolide-induced cell death in human prostatic adenocarcinoma PC-3 cells. 1587 75

Most tumor cells are sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis but sparing to normal cells, thus providing therapeutic potential for clinical use. Some tumor cells are resistant to TRAIL-induced cell death while the sensitivity could be recruited with the existence of some chemical agents. In this study, human prostatic cancer cell line LNCaP was found to be resistant to TRAIL-induced apoptosis while it could be restored to TRAIL sensitivity with combination treatment of low concentration of doxorubicin. TRAIL receptor-1 (DR4) and TRAIL receptor-2 (DR5) were upregulated under the treatment of doxorubicin and verified to be responsible for TRAIL-mediated signal transduction. Furthermore, caspase-8 and caspase-3 were activated and drove their autocleavage into programmed cell death. Interestingly, apoptosis-inhibitory protein c-FLIP, but not Bcl-2 and XIAP was downregulated after doxorubicin treatment. Taken together, these findings suggested that the pathway of cell apoptosis induced by TRAIL was intact but under negative control. Subtoxic concentration of doxorubicin effectively boosted TRAIL sensitivity via depletion of antiapoptotic protein. These findings support the new strategies for killing tumors with TRAIL and chemical agents.
Prostate Cancer Prostatic Dis 2005
PMID:Subtoxic concentration of doxorubicin enhances TRAIL-induced apoptosis in human prostate cancer cell line LNCaP. 1589 17


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