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.
Bibliographical noteFunding Information:
This work was supported by National Research Foundation Grants (2014R1A2A2A01002448, 2015R1A 1A3A04001339, 2015R1A2A1A15051678 and 2016R1 A6A3A01006416), a grant from the BK21 plus Program, and grants from Kangwon National University (120150086 and 520160302).
- Anti-cancer drug-resistance