title: Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia.
abstract: Methylseleninic acid (MSeA) is a monomethylated selenium metabolite theoretically derived from subsequent β-lyase or transamination reactions of dietary Se-methylselenocysteine that has potent antitumor activity by inhibiting cell proliferation of several cancers. Our previous studies showed that MSeA promotes apoptosis in invasive prostate cancer cells in part by downregulating hypoxia-inducible factor HIF-1α. We have now extended these studies to evaluate the impact of MSeA on REDD1 (an mTOR inhibitor) in inducing cell death of invasive prostate cancer cells in hypoxia. In both PTEN+ and PTEN- prostate cancer cells we show that MSeA elevates REDD1 and phosphorylation of AKT along with p70S6K in hypoxia. Furthermore, REDD1 induction by MSeA is independent of AKT and the mTOR inhibition in prostate cancer cells causes partial resistance to MSeA-induced growth reduction in hypoxia. Our data suggest that MSeA induces REDD1 and inhibits prostate cancer cell growth in hypoxia despite activation of AKT and dysregulation of mTOR.
authors: Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.
authors: Indu
authors: I
authors: Sinha
authors: Joshua E
authors: JE
authors: Allen
authors: John T
authors: JT
authors: Pinto
authors: Raghu
authors: R
authors: Sinha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C469991:DDIT4 protein, human; C469992:Ddit4 protein, mouse; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C008493:methylselenic acid; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Methylseleninic acid; REDD1; prostate cancer