Research Papers:
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
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Abstract
Youngmi Kim1,*, Hyuna Kim1,*, Deokbum Park1, Hansoo Lee2, Yun Sil Lee3, Jongseon Choe4, Young Myeong Kim4, Doyong Jeon5, Dooil Jeoung1
1Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 24341, Korea
2Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chunchon 24341, Korea
3College of Pharmacy, Ewha Womans University, Seoul 03760, Korea
4Graduate School of Medicine, Kangwon National University, Chunchon 24341, Korea
5L-Base Company, Seoul 01062, Korea
*These authors contributed equally to this work
Correspondence to:
Dooil Jeoung, email: [email protected]
Keywords: anti-cancer drug-resistance, CAGE, cyclinD1, GSK3β, peptides
Received: February 12, 2016 Accepted: January 03, 2017 Published: January 13, 2017
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.
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