Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Neoplastic transformation of prostate epithelium involves aberrant activation of anti-apoptotic and pro-invasive pathways triggered by multiple poorly understood genetic events. We demonstrated earlier that depletion of mitochondrial DNA (mtDNA) induces prostate cancer progression. Here, using normal prostate epithelial PNT1A cells we demonstrate that mtDNA depletion prevents detachment-induced apoptosis (anoikis) and promotes migratory capabilities onto basement membrane proteins through upregulation of p85 and p110 phosphatidylinositol 3-kinase (PI3K) subunits, which results in Akt2 activation and phosphorylation of downstream substrates GSK3beta, c-Myc, MMP-9, Mdm2, and p53. Pharmacological or genetic PI3K inhibition, siRNA-mediated Akt2 depletion, as well as mtDNA reconstitution were sufficient to restore sensitivity to anoikis and curtail cell migration. Moreover, Akt2 activation induced glucose transporter 1 (GLUT1) expression, glucose uptake, and lactate production, common phenotypic changes seen in neoplastic cells. In keeping with these findings, several prostate carcinoma cell lines displayed reduced mtDNA content and increased PI3K/Akt2 levels when compared to normal PNT1A cells, and Akt2 downregulation prevented their survival, migration and glycolytic metabolism. On a tissue microarray, we also found a statistically significant decrease in mtDNA-encoded cytochrome oxidase I in prostate carcinomas. Taken together, these results provide novel mechanistic evidence supporting the notion that mtDNA mutations may confer survival and migratory advantage to prostate cancer cells through Akt2 signaling.
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PMID:Mitochondrial DNA depletion in prostate epithelial cells promotes anoikis resistance and invasion through activation of PI3K/Akt2. 1907 38

Aberrant Ras and Wnt signaling are emerging as key events in the multistep nature of prostate tumorigenesis and progression. Here, we report the generation of a compound model of prostate cancer to define the synergism of activated K-ras (K-ras(+/V12)) and dominant stabilized beta-catenin (Catnb(+/lox(ex3))) in the murine prostate. Recombination of floxed alleles and subsequent expression of oncogenic transgenes was mediated by Cre recombinase expression governed by the composite Probasin (PB) promoter (termed PBCre). Concomitant with elevated mitogen-activated protein kinase (MAPK) signaling, PBCre(+)K-ras(+/V12) mice developed AH at 100 days (100% incidence) and low-grade prostate intraepithelial neoplasia and adenocarcinoma (60% and 7% incidence) by 500 days. PBCre(+)Catnb(+/lox(ex3)) mice showed reduced longevity (average 428 days) and were predisposed to PIN-like keratinized squamous metaplasia at 100 days (100% incidence) and adenocarcinoma (100% incidence) at end-point. These lesions displayed elevated Wnt signaling and basal levels of MAPK signaling. Synchronous activation of K-ras and beta-catenin significantly reduced survival (average 189 days), reflecting accelerated tumorigenesis and the development of invasive carcinoma that displayed activated Wnt and MAPK signaling. Notably, expression of the basal cell marker p63 negatively correlated with tumor grade, resembling human prostate adenocarcinoma. Taken together, our data show that combinatorial oncogenic mutations of K-ras and beta-catenin drive rapid progression of prostate tumorigenesis to invasive carcinoma, characterized by the synergistic elevation of androgen receptor, cyclooxygenase-2, and c-Myc.
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PMID:K-ras and Wnt signaling synergize to accelerate prostate tumorigenesis in the mouse. 1911 91

There is an inverse correlation between exposure to sunlight (the major source of vitamin D) and the risk for prostate cancer, the most common noncutaneous cancer and second most common cause of death from cancer in American men. The active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] acting through the vitamin D receptor decreases prostate cancer cell growth and invasiveness. The precise mechanisms by which 1,25(OH)(2)D(3) inhibits growth in prostate cancer have not been fully elucidated. Treatment with 1,25(OH)(2)D(3) causes an accumulation in the G(0)/G(1) phase of the cell cycle in several prostate cancer cell lines. One potential target known to regulate the G(0)/G(1) to S phase transition is c-Myc, a transcription factor whose overexpression is associated with a number of cancers including prostate cancer. We find that 1,25(OH)(2)D(3) reduces c-Myc expression in multiple prostate epithelial cell lines, including C4-2 cells, an androgen-independent prostate cancer cell line. Reducing c-Myc expression to the levels observed after 1,25(OH)(2)D(3) treatment resulted in a comparable decrease in proliferation and G(1) accumulation demonstrating that down-regulation of c-Myc is a major component in the growth-inhibitory actions of 1,25(OH)2D(3). Treatment with 1,25(OH)(2)D(3) resulted in a 50% decrease in c-Myc mRNA but a much more extensive reduction in c-Myc protein. Treatment with 1,25(OH)(2)D(3) decreased c-Myc stability by increasing the proportion of c-Myc phosphorylated on T58, a glycogen synthase kinase-3beta site that serves as a signal for ubiquitin-mediated proteolysis. Thus, 1,25(OH)(2)D(3) reduces both c-Myc mRNA levels and c-Myc protein stability to inhibit growth of prostate cancer cells.
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PMID:1Alpha,25-dihydroxyvitamin D3 reduces c-Myc expression, inhibiting proliferation and causing G1 accumulation in C4-2 prostate cancer cells. 1916 69

Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen. Notwithstanding the renewed interest in the Warburg effect, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine, which is highly transported into proliferating cells, is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood. Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. This leads to upregulation of glutamine catabolism. Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis. The unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis.
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PMID:c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. 1921 26

Epidemiologic evidence suggests that a diet rich in fruits and vegetables is associated with a reduced risk of prostate cancer (PCa) development. Although several dietary compounds have been tested in preclinical PCa prevention models, no agents have been identified that either prevent the progression of premalignant lesions or treat advanced disease. Momordica charantia, known as bitter melon in English, is a plant that grows in tropical areas worldwide and is both eaten as a vegetable and used for medicinal purposes. We have isolated a protein, designated as MCP30, from bitter melon seeds. The purified fraction was verified by SDS-PAGE and mass spectrometry to contain only 2 highly related single chain Type I ribosome-inactivating proteins (RIPs), alpha-momorcharin and beta-momorcharin. MCP30 induces apoptosis in PIN and PCa cell lines in vitro and suppresses PC-3 growth in vivo with no effect on normal prostate cells. Mechanistically, MCP30 inhibits histone deacetylase-1 (HDAC-1) activity and promotes histone-3 and -4 protein acetylation. Treatment with MCP30 induces PTEN expression in a prostatic intraepithelial neoplasia (PIN) and PCa cell lines resulting in inhibition of Akt phosphorylation. In addition, MCP30 inhibits Wnt signaling activity through reduction of nuclear accumulation of beta-catenin and decreased levels of c-Myc and Cyclin-D1. Our data indicate that MCP30 selectively induces PIN and PCa apoptosis and inhibits HDAC-1 activity. These results suggest that Type I RIPs derived from plants are HDAC inhibitors that can be utilized in the prevention and treatment of prostate cancer.
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PMID:Ribosome-inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase-1 selectively in premalignant and malignant prostate cancer cells. 1938 52

Epidemiology supports the important role of nutrition in prostate cancer (PCa) prevention. Pomegranate juice (PJ) exerts protective effects against PCa, mainly attributed to PJ ellagitannins (ETs). Our aim was to assess whether ETs or their metabolites ellagic acid and urolithins reach the human prostate upon consumption of ET-rich foods and to evaluate the effect on the expression of three proliferation biomarkers. Sixty-three patients with BPH or PCa were divided into controls and consumers of walnuts (35 g walnuts/day) or pomegranate (200 mL PJ/day) for 3 days before surgery. Independently of the ETs source, the main metabolite detected was urolithin A glucuronide, (3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide) (up to 2 ng/g) together with the traces of urolithin B glucuronide, (3-hydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide) and dimethyl ellagic acid. The small number of prostates containing metabolites was likely caused by clearance of the compounds during the fasting. This was corroborated in a parallel rat study and thus the presence of higher quantities of metabolites at earlier time points cannot be discarded. No apparent changes in the expression of CDKN1A, MKi-67 or c-Myc were found after consumption of the walnuts or PJ. Our results suggest that urolithin glucuronides and dimethyl ellagic acid may be the molecules responsible for the beneficial effects of PJ against PCa.
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PMID:Occurrence of urolithins, gut microbiota ellagic acid metabolites and proliferation markers expression response in the human prostate gland upon consumption of walnuts and pomegranate juice. 1988 50

The forced overexpression of c-Myc in mouse prostate and in normal human prostate epithelial cells results in tumor transformation with an invasive phenotype. How c-Myc regulates cell invasion is poorly understood. In this study, we have investigated the interplay of c-Myc and androgens in the regulation of prostate cancer cell invasion. We found that c-Myc induces cell invasion and anchorage-independent growth by regulating ezrin protein expression in the presence of androgens. The activity of the ezrin promoter is controlled by androgens through c-Myc, which binds to a phylogenetically conserved E-Box located in the proximal promoter region. Besides, we also show that ezrin is an important regulator of c-Myc protein levels. These effects are achieved through androgen-induced changes in ezrin phosphorylation, which results in the regulation of downstream signals. These downstream signals involve the modulation of Akt and GSK-3beta activity resulting in increased c-Myc protein synthesis and inhibition of its degradation. In summary, we have shown a key role for ezrin as a mediator of c-Myc-induced tumorigenesis in prostate cancer cells.
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PMID:Ezrin mediates c-Myc actions in prostate cancer cell invasion. 2001 Aug 76

Activation of the serine/threonine kinase Akt is associated with aggressive clinical behavior of prostate cancer. We found that the human prostate cancer cell lines LNCaP and PC-3 express predominantly Akt1 and Akt2. Selective down-regulation of Akt1, but not Akt2, by short-hairpin RNA reduced the viability of prostate cancer cells. In addition, structurally different Akt inhibitors were cytotoxic for the prostate cancer cells, confirming that the Akt pathway is indispensable for their viability. We have purified the tetracyclic triterpenoids 3-oxo-tirucallic acid, 3-alpha-acetoxy-tirucallic acid, and 3-beta-acetoxy-tirucallic acid from the oleogum resin of Boswellia carterii to chemical homogeneity. The acetoxy-derivatives in particular potently inhibited the activities of human recombinant Akt1 and Akt2 and of constitutively active Akt immunoprecipitated from PC-3 cells, whereas inhibitor of nuclear factor-kappaB kinases remained unaffected. Docking data indicated that these tetracyclic triterpenoids form hydrogen bonds within the phosphatidylinositol binding pocket of the Akt pleckstrin homology domain. Accordingly, 3-beta-acetoxy-tirucallic acid did not inhibit the activity of Akt1 lacking the pleckstrin homology domain. In the prostate cancer cell lines investigated, these compounds inhibited the phosphorylation of cellular Akt and the Akt signaling pathways, including glycogen synthase kinase-3beta and BAD phosphorylation, nuclear accumulation of p65, the androgen receptor, beta-catenin, and c-Myc. These events culminated in the induction of apoptosis in prostate cancer, but not in nontumorigenic cells. The tirucallic acid derivatives inhibited proliferation and induced apoptosis in tumors xenografted onto chick chorioallantoic membranes and decreased the growth of pre-established prostate tumors in nude mice without overt systemic toxicity. Thus, tirucallic acid derivatives represent a new class of Akt inhibitors with antitumor properties.
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PMID:Tirucallic acids are novel pleckstrin homology domain-dependent Akt inhibitors inducing apoptosis in prostate cancer cells. 2001 12

Artemisinin is a plant-derived anti-malarial drug that has relatively low toxicity in humans and is activated by heme and/or intracellular iron leading to intracellular free radical formation. Interestingly, artemisinin has displayed anti-cancer activity, with artemisinin dimers being more potent than monomeric artemisinin. Intracellular iron uptake is regulated by the transferrin receptor (TfR), and the activity of artemisinin depends on the availability of iron. We examined the level of TfR in prostate cancer (PCa) tumor cells, synthesized two new artemisinin dimers, and evaluated the effect of dihydroartemisinin and artemisinin dimers, ON-2Py and 2Py, on proliferation and apoptosis in PCa cells. TfR was expressed in the majority of PCa bone and soft tissue metastases, all 24 LuCaP PCa xenografts, and PCa cell lines. After treatment with dihydroartemisinin, ON-2Py, or 2Py all PCa cell lines displayed dose-dependent decrease in cell number. 2Py was most effective in decreasing cell number. An increase in apoptotic events and growth arrest was observed in the C4-2 and LNCaP cell lines. Growth arrest was observed in PC-3 cells, but no significant change was observed in DU 145 cells. Treatment with 2Py resulted in a loss of the anti-apoptotic protein survivin in all four cell lines. 2Py treatment also decreased androgen receptor and prostate-specific antigen expression in C4-2 and LNCaP cells, with a concomitant loss of cell cycle regulatory proteins cyclin D1 and c-Myc. This study shows the potential use of artemisinin derivatives as therapeutic candidates for PCa and warrants the initiation of preclinical studies.
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PMID:Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells. 2013 Apr 67

Vitamin D receptor (VDR) agonists have been shown to reduce the growth of several prostate cancer cell lines. However, the effects of VDR activation have not been examined in the presence of the recently identified androgen-regulated TMPRSS2:ERG gene fusions, which occur in a high percentage of prostate cancers and play a role in growth and invasiveness. In a previous microarray study, we found that VDR activation induces TMPRSS2 expression in LNCaP prostate cancer cells. Here we show that the natural VDR agonist 1alpha,25-dihydroxyvitamin D(3) and its synthetic analog EB1089 increase expression of TMPRSS2:ERG mRNA in VCaP prostate cancer cells; this results in increased ETS-related gene (ERG) protein expression and ERG activity as demonstrated by an increase in the ERG target gene CACNA1D. In VCaP cells, we were not able to prevent EB1089-mediated TMPRSS2:ERG induction with an androgen receptor antagonist, Casodex, although in LNCaP cells, as reported for some other common androgen receptor and VDR target genes, Casodex reduces EB1089-mediated induction of TMPRSS2. However, despite inducing the fusion gene, VDR agonists reduce VCaP cell growth and expression of the ERG target gene c-Myc, a critical factor in VDR-mediated growth inhibition. Thus, the beneficial effects of VDR agonist treatment override some of the negative effects of ERG induction, although others remain to be tested.
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PMID:1{alpha},25-Dihydroxyvitamin D3 inhibits growth of VCaP prostate cancer cells despite inducing the growth-promoting TMPRSS2:ERG gene fusion. 2014 25


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