title: Identification of glycogen synthase kinase 3α as a therapeutic target in melanoma.
abstract: Deregulated expression or activity of kinases can lead to melanomas, but often the particular kinase isoform causing the effect is not well established, making identification and validation of different isoforms regulating disease development especially important. To accomplish this objective, an siRNA screen was undertaken that which identified glycogen synthase kinase 3α (GSK3α) as an important melanoma growth regulator. Melanocytes and melanoma cell lines representing various stages of melanoma tumor progression expressed both GSK3α and GSK3β, but analysis of tumors in patients with melanoma showed elevated expression of GSK3α in 72% of samples, which was not observed for GSK3β. Furthermore, 80% of tumors in patients with melanoma expressed elevated levels of catalytically active phosphorylated GSK3α (pGSK3αY279), but not phosphorylated GSK3β (pGSK3βY216). siRNA-mediated reduction in GSK3α protein levels reduced melanoma cell survival and proliferation, sensitized cells to apoptosis-inducing agents and decreased xenografted tumor development by up to 56%. Mechanistically, inhibiting GSK3α expression using siRNA or the pharmacological agent AR-A014418 arrested melanoma cells in the G0/G1 phase of the cell cycle and induced apoptotic death to retard tumorigenesis. Therefore, GSK3α is a key therapeutic target in melanoma.
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: SubbaRao V
authors.initials: SV
authors.lastname: Madhunapantula
authors.forename: Arati
authors.initials: A
authors.lastname: Sharma
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Gowda
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D034741:RNA, Small Interfering / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: GSK3 α; GSK3 β; kinase targets; malignant melanoma; siRNA library screening
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