title: Methylseleninic acid downregulates hypoxia-inducible factor-1α in invasive prostate cancer.
abstract: Alternative strategies are needed to control growth of advanced and hormone refractory prostate cancer. In this regard, we investigated the efficacy of methylseleninic acid (MSeA), a penultimate precursor to the highly reactive selenium metabolite, methylselenol, to inhibit growth of invasive and hormone refractory rat (PAIII) and human (PC-3 and PC-3M) prostate cancer cells. Our results demonstrate that MSeA inhibits PAIII cell growth in vitro as well as reduces weights of tumors generated by PAIII cells treated ex vivo. A significant reduction in the number of metastatic lung foci by MSeA treatment was also noted in Lobund-Wistar rats. The PAIII cells along with PC-3, DU145 and PC-3M cells undergo apoptosis after MSeA treatments in both normoxia and hypoxia. Treatment of metastatic rat and human prostate cancer cell lines with MSeA decreased hypoxia-inducible factor-1α (HIF-1α) levels in a dose-dependent manner. Additionally, HIF-1α transcription activity both in normoxic and hypoxic conditions is reduced after MSeA treatment of prostate cancer cells. Furthermore, VEGF and GLUT1, downstream targets of HIF-1α, were also reduced in prostate cancer cells after MSeA treatment. Our study illustrates the efficacy of MSeA in controlling growth of hormone refractory prostate cancer by downregulating HIF-1α, which is possibly occurring through stabilization or increase in prolyl hydroxylase activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Indu
authors.initials: I
authors.lastname: Sinha
authors.forename: Kevin
authors.initials: K
authors.lastname: Null
authors.forename: William
authors.initials: W
authors.lastname: Wolter
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Tonya
authors.initials: T
authors.lastname: King
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.forename: Raghu
authors.initials: R
authors.lastname: Sinha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D009362:Neoplasm Metastasis; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012643:Selenium / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016566:Organoselenium Compounds; C495679:Slc2a1 protein, rat; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C008493:methylselenic acid; D011393:Procollagen-Proline Dioxygenase; D012643:Selenium