title: The pentapeptide Gly-Thr-Gly-Lys-Thr confers sensitivity to anti-cancer drugs by inhibition of CAGE binding to GSK3β and decreasing the expression of cyclinD1.
abstract: We previously reported the role of cancer/testis antigen CAGE in the response to anti-cancer drugs. CAGE increased the expression of cyclinD1, and pGSK3βSer9, an inactive GSK3β, while decreasing the expression of phospho-cyclinD1Thr286. CAGE showed binding to GSK3β and the domain of CAGE (amino acids 231-300) necessary for binding to GSK3β and for the expression regulation of cyclinD1 was determined. 269GTGKT273 peptide, corresponding to the DEAD box helicase domain of CAGE, decreased the expression of cyclinD1 and pGSK3βSer9 while increasing the expression of phospho-cyclinD1Thr286. GTGKT peptide showed the binding to CAGE and prevented CAGE from binding to GSK3β. GTGKT peptide changed the localization of CAGE and inhibited the binding of CAGE to the promoter sequences of cyclin D1. GTGKT peptide enhanced the apoptotic effects of anti-cancer drugs and decreased the migration, invasion, angiogenic, tumorigenic and metastatic potential of anti-cancer drug-resistant cancer cells. We found that Lys272 of GTGKT peptide was necessary for conferring anti-cancer activity. Peptides corresponding to the DEAD box helicase domain of CAGE, such as AQTGTGKT, QTGTGKT and TGTGKT, also showed anti-cancer activity by preventing CAGE from binding to GSK3β. GTGKT peptide showed ex vivo tumor homing potential. Thus, peptides corresponding to the DEAD box helicase domain of CAGE can be developed as anti-cancer drugs in cancer patients expressing CAGE.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 24341, Korea.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 24341, Korea.
authors.forename: Hyuna
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 24341, Korea.
authors.forename: Deokbum
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chunchon 24341, Korea.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 03760, Korea.
authors.forename: Yun Sil
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Graduate School of Medicine, Kangwon National University, Chunchon 24341, Korea.
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
authors.affiliation: Graduate School of Medicine, Kangwon National University, Chunchon 24341, Korea.
authors.forename: Young Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: L-Base Company, Seoul 01062, Korea.
authors.forename: Doyong
authors.initials: D
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 24341, Korea.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D000072417:Protein Domains
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; D009842:Oligopeptides; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C454199:DDX53 protein, human; D053487:DEAD-box RNA Helicases
keywords: CAGE; GSK3β; anti-cancer drug-resistance; cyclinD1; peptides