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)

In this study, we investigated the functional role of early growth response-1 (Egr1 gene) in the regulation of radiation-induced clonogenic inhibition and apoptosis in p53 wild-type and mutant prostate cancer cells 22Rv1 and DU145, respectively. 22Rv1 cells were more sensitive to irradiation compared with DU145 cells, and the sensitivity was enhanced by overexpression of EGR-1 in both cells. Dominant-negative EGR-1 mutant (dnEGR-1) or repressor of EGR-1, NGFIA binding protein 1 (NAB1), increased radioresistance of these cells. Significant activation of caspases 3 and 9 and Bcl2-associated X (Bax) with increased poly(ADP-ribose) polymerase (PARP) cleavage and cytochrome c release was observed in radiation-exposed EGR-1 overexpressing cells. Gel shift analysis and chloramphenicol acetyl transferase (CAT) reporter assays indicate that EGR-1 transactivates the promoter of the Bax gene. Interaction of EGR-1 and Yes kinase-associated protein 1 (YAP-1) through the WW domain of YAP-1 enhances the transcriptional activity of EGR-1 on the Bax promoter as shown by chromatin immunoprecipitation and reporter assays. Irradiation of PC3 cell xenografts that were treated with adenoviral EGR-1 showed significant regression in tumor volume. These findings establish the radiation-induced pro-apoptotic action of EGR-1, in a p53-independent manner, by directly transactivating Bax, and prove that alters the B-cell CLL/lymphoma 2 (Bcl-2)/Bax ratio as one of the mechanisms resulting in significant activation of caspases, leading to cell death through the novel interaction of EGR-1 with YAP-1.
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PMID:EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells. 1913 13

It has been recently demonstrated that small gold compounds could have a potential anti-tumoral activity. Here, we report that aurothiomalate (ATM), a gold compound already used in clinical therapy for the treatment of rheumatoid arthritis, has a pro-apoptotic effect in aggressive prostate cancer (PC3U) cells. In contrast, treatment of human primary epithelial prostate cells (PrEC) with ATM did not cause apoptosis. We demonstrated that ATM is able to disrupt the PKCiota-Par6 complex in PC3U cells and that this disruption leads to the activation of ERK in a dose-dependent manner. Interestingly, we also showed that ERK acts upstream of the activation of caspase 3, leading to apoptosis. ATM treatment also causes activation of p38 and JNK MAP kinases. Moreover we could link ATM treatment to activation of the mitochondrial or so called intrinsic pathway, as we observed release of cytochrome c from mitochondria to cytoplasm, suggesting that the mitochondrial pathway is involved in the pro-apoptotic effect mediated by ATM. Taken together our data suggest that ATM could be a new promising drug for the treatment of advanced prostate cancer.
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PMID:Pro-apoptotic effect of aurothiomalate in prostate cancer cells. 1916 22

We observed that treatment of prostate cancer cells for 24 h with magnolol, a phenolic component extracted from the root and stem bark of the oriental herb Magnolia officinalis, induced apoptotic cell death in a dose- and time-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in magnolol-treated cells. Treatment of PC-3 cells with an apoptosis-inducing concentration of magnolol (60 microM) resulted in a rapid decrease in the level of phosphorylated Akt leading to inhibition of its kinase activity. Magnolol treatment (60 microM) also caused a decrease in Ser((136)) phosphorylation of Bad (a proapoptotic protein), which is a downstream target of Akt. Protein interaction assay revealed that Bcl-xL, an anti-apoptotic protein, was associated with Bad during treatment with magnolol. We also observed that during treatment with magnolol, translocation of Bax to the mitochondrial membrane occurred and the translocation was accompanied by cytochrome c release, and cleavage of procaspase-8, -9, -3, and poly(ADP-ribose) polymerase (PARP). Similar results were observed in human colon cancer HCT116Bax(+/-) cell line, but not HCT116Bax(-/-) cell line. Interestingly, at similar concentrations (60 microM), magnolol treatment did not affect the viability of normal human prostate epithelial cell (PrEC) line. We also observed that apoptotic cell death by magnolol was associated with significant inhibition of pEGFR, pPI3K, and pAkt. These results suggest that one of the mechanisms of the apoptotic activity of magnolol involves its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways.
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PMID:Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells. 1922 60

Apoptosis, a form of cell death, is a fundamental process for the development and maintenance of multicellular organisms that promotes the removal of damaged, senescent or unwanted cells. Induction of cancer cell apoptosis is an important strategy of anticancer therapy. In this study, we examined if melatonin, the main secretory product of the pineal gland, inhibited the growth of prostate cancer cells (LNCaP) and promoted apoptosis via mitogen-activated protein kinases (MAPKs), which are closely associated with apoptosis and survival. Melatonin treatment significantly inhibited the growth of LNCaP cells in a dose- and time-dependent manner. It clearly induced both an early stage of apoptosis (propidium iodide(-), FITC Annexin-V(+)) and a late apoptosis/secondary necrosis (propidium iodide(+) and FITC Annexin-V(+)), which indicated induction of serial stages of apoptosis in cells. Moreover, melatonin markedly activated c-JUN N-terminal kinase (JNK) and p38 kinase, whereas extracellular signal-regulated kinase (ERK) was not responsive to melatonin. Treatment with MAPK inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor), confirmed that melatonin-induced apoptosis was JNK- and p38-dependent, but ERK-independent. In the presence of PD98059, caspase-3 activity increased, while levels of Bax/cytochrome c (Cyt c) and Bcl-2 decreased. These effects were opposite to those observed with SP600125 and SB202190 treatments. Together, these results strongly suggest that JNK and p38 activation directly participate in apoptosis induced by melatonin. Thus, melatonin may be of promise for anti-prostate cancer strategies.
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PMID:Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer. 1952 39

Three new butanolides, tenuifolide A (1), isotenuifolide A (2), and tenuifolide B (3), a new secobutanolide, secotenuifolide A (4), and one new sesquiterpenoid, tenuifolin (5), along with 16 known compounds were isolated from the stems of Cinnamomum tenuifolium. Their structures were determined by spectroscopic analyses. Compound 4 was found to induce apoptotic-related DNA damage, increase sub-G1 cells, and inhibit the growth of human prostate cancer cells, DU145. In addition, treatment with 4 significantly increased intracellular H2O2 and/or peroxide. The results show that 4 induced (a) noticeable reduction of mitochondrial transmembrane potential (DeltaPsim); (b) significant increase in the ratio of cytochrome c concentration (cytosol/mitochondria); and (c) subsequent activation of caspase-9/caspase-3. Antiproliferation caused by 4 was found to markedly decrease when pretreated with caspase-9/caspase-3 inhibitor. In ROS scavenging, antioxidant, NADPH oxidase, and NO inhibitor studies, pretreatment of DU145 cells with either DPI, dexamethasone, L-NAME, or mannitol decreased 4-induced intracellular DCF fluorescence of ROS. These results suggest that an increase of H2O2 and/or peroxide by 4 is the initial apoptotic event and 4 has anticancer effects on DU145 cells.
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PMID:Cytotoxic compounds from the stems of Cinnamomum tenuifolium. 1975 30

CDDO-Me, a synthetic triterpenoid derived from oleanolic acid, is a promising anticancer agent that has shown strong activity against a wide variety of cancer types in vitro and in vivo. We have previously shown that CDDO-Me induces apoptosis in prostate cancer cells irrespective of their hormonal status. To further understand the proapoptotic mechanism of CDDO-Me, we investigated the role of reactive oxygen species (ROS) in mediating the apoptosis inducing activity of CDDO-Me in LNCaP and PC-3 prostate cancer cell lines. Here, we show that CDDO-Me induces ROS generation from both nonmitochondrial and mitochondrial sources, which is associated with the induction of apoptosis as characterized by increased annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c. In addition, CDDO-Me inhibited cell survival Akt, NF-kappaB and mTOR signaling proteins. The inhibition of ROS generation by N-acetylcysteine (NAC) or by overexpression of antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase-1 (SOD-1) prevented CDDO-Me-induced apoptosis. Pretreatment with NAC blocked annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c by CDDO-Me. NAC also prevented the inhibition of constitutively active Akt, NF-kappaB and mTOR by CDDO-Me. Together, these data indicate that ROS plays an essential role in the induction of apoptosis by CDDO-Me in prostate cancer cells.
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PMID:Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. 1978 51

Piceatannol (trans-3,4,3',5'-tetrahydroxystilbene) is a polyphenol that is found in grapes, red wine, Rheum undulatum, and the seeds of Euphorbia lagascae. It has been previously reported that piceatannol inhibits the proliferation of a variety of cancer cell types. In the present study, we assessed the effects of piceatannol on the growth of androgen-insensitive DU145 prostate cancer cells at concentrations of 1-10 micromol/L. Piceatannol reduced the viable numbers and increased the numbers of apoptotic DU145 cells in a dose-dependent manner. Western blot analysis revealed that piceatannol increased the protein levels of cleaved caspase-8, -9, -7, and -3 and cleaved poly(ADP-ribose) polymerase (PARP). Piceatannol increased mitochondrial membrane permeability and cytochrome c release from the mitochondria to the cytosol. Piceatannol induced an increase in the levels of truncated Bid, Bax, Bik, Bok, and Fas but caused a decrease in the levels of Mcl-1 and Bcl-xL. Caspase-8 and -9 inhibitors mitigated piceatannol-induced apoptosis. The caspase-8 inhibitor suppressed the piceatannol-induced cleavage of Bid, caspase-3, and PARP. These results indicate that piceatannol induces apoptosis via the activation of the death receptor and mitochondrial-dependent pathways in prostate cancer cells.
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PMID:The grape component piceatannol induces apoptosis in DU145 human prostate cancer cells via the activation of extrinsic and intrinsic pathways. 1985 55

Resistance to anticancer agents is one of the primary impediments to effective cancer therapy. Chemoresistance occurs not only to clinically established therapeutic agents but also to novel targeted therapeutics. Both intrinsic and acquired mechanisms have been implicated in drug resistance but it remains controversial which mechanisms are responsible that lead to failure of therapy in cancer patients. Recent focus has turned to clusterin (CLU) as a key contributor to chemoresistance to anticancer agents. Its role has been documented in prostate cancer for paclitaxel/docetaxel resistance as well as in renal, breast, and lung tumor cells. Moreover, it is abnormally upregulated in numerous advanced stage and metastatic cancers spanning prostate, renal, bladder, breast, head and neck, colon, cervical, pancreatic, lung carcinomas, melanoma, and lymphoma. It is noteworthy that only the cytoplasmic/secretory clusterin form (sCLU), and not the nuclear form, is expressed in aggressive late stage tumors, which is in line with its antiapoptotic function. Most significantly, sCLU expression is documented to lead to broad-based resistance to other unrelated chemotherapeutic agents such as doxorubicin, cisplatin, etoposide, and camphothecin. Resistance to targeted death-inducing molecules, tumor necrosis factor, Fas and TRAIL, or histone deacetylase inhibitors can also be mediated by sCLU. Expression of sCLU may be an adaptive response to genotoxic and oxidative stresses but this adaptive response could pose a threat in malignant cells being treated with cytotoxic agents by enhancing their survival potential. The actual mechanisms for sCLU induction are unclear but STAT1 is required for its constitutive upregulation in docetaxel-resistant tumor cells. Known as a protein chaperone, sCLU appears to stabilize Ku70/Bax complexes, sequestering Bax from its ability to induce mitochondrial release of cytochrome c that triggers cell apoptosis. Thus, sCLU has a key role in preventing apoptosis induced by cytotoxic agents and has the potential to be targeted for cancer therapy.
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PMID:Clusterin and chemoresistance. 1987 24

Prostate cancer is the leading cause of cancer-related death in men, incidences of which are increasing gradually in India. Protein kinase C (PKC), an enzyme, gets overexpressed in prostate cancer and results in a resistance to chemotherapy. Telomerase, a reverse transcriptase, is highly activated in prostate cancer cells. Both of these enzymes can be considered as potential molecular markers for prostate cancer. The present study investigates the effects of natural isothiocyanate phenethyl isothiocyanate (PEITC) in modulating the activities of PKC and telomerase in the androgen-independent human prostate adenocarcinoma (PC-3) cell line. We observed that PEITC downregulated the antiapoptotic isoforms (PKC alpha and epsilon) efficiently and zeta moderately. Basal level of PKC delta, a proapoptotic form, was very poor and its modulation was not significant. PEITC also inhibited the activity of telomerase. Studies were conducted to measure the degree of apoptotic cell death induced either by PEITC alone or in combination with adriamycin or etoposide. Apoptosis was evident from the release of mitochondrial cytochrome c, apoptotic index, and by the induction of caspases 3 and 8. PEITC exhibited remarkable efficacy in sensitizing PC-3 cells to undergo cell death by adriamycin and etoposide, which might prove to be of considerable value in synergistic therapy of cancer.
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PMID:Targeting protein kinase C (PKC) and telomerase by phenethyl isothiocyanate (PEITC) sensitizes PC-3 cells towards chemotherapeutic drug-induced apoptosis. 2010 25

The physical manifestations of aging reflect a loss of homeostasis that effects molecular, cellular and organ system functional capacity. As a sentinel homeostatic pathway, changes in apoptosis can have pathophysiological consequences in both aging and disease. To assess baseline global apoptosis balance, sera from 204 clinically normal subjects had levels of sFas (inhibitor of apoptosis), sFasL (stimulator of apoptosis), and total cytochrome c (released from cells during apoptosis) measured. Serum levels of sFas were significantly higher while sFasL and cytochrome c levels were lower in men compared to women. With increasing age there was a decrease in apoptotic markers (cytochrome c) and pro-apoptotic factors (sFasL) and an increase in anti-apoptotic factors (sFas) in circulation. The observed gender differences are consistent with the known differences between genders in mortality and morbidity. In a separate cohort, subjects with either breast (n = 66) or prostate cancer (n = 38) exhibited significantly elevated sFas with reduced sFasL and total cytochrome c regardless of age. These markers correlated with disease severity consistent with tumor subversion of apoptosis. The shift toward less global apoptosis with increasing age in normal subjects is consistent with increased incidence of diseases whose pathophysiology involves apoptosis dysregulation.
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PMID:Serum markers of apoptosis decrease with age and cancer stage. 2015 46


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