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

Youngmi Kim; Hyuna Kim; Deokbum Park; Hansoo Lee; Yun Sil Lee; Jongseon Choe; Young Myeong Kim; Doyong Jeon; Dooil Jeoung

doi:10.18632/oncotarget.14618

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

Youngmi Kim, Hyuna Kim, Deokbum Park, Hansoo Lee, Yun Sil Lee, Jongseon Choe, Young Myeong Kim, Doyong Jeon, Dooil Jeoung

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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 pGSK3β^Ser9, 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 pGSK3β^Ser9 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.

Original language	English
Pages (from-to)	13600-13619
Number of pages	20
Journal	Oncotarget
Volume	8
Issue number	8
DOIs	https://doi.org/10.18632/oncotarget.14618
State	Published - 2017

Bibliographical note

Funding 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).

Keywords

Anti-cancer drug-resistance
CAGE
CyclinD1
GSK3β
Peptides

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10.18632/oncotarget.14618

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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.",

keywords = "Anti-cancer drug-resistance, CAGE, CyclinD1, GSK3β, Peptides",

author = "Youngmi Kim and Hyuna Kim and Deokbum Park and Hansoo Lee and Lee, {Yun Sil} and Jongseon Choe and Kim, {Young Myeong} and Doyong Jeon and Dooil Jeoung",

note = "Funding 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).",

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doi = "10.18632/oncotarget.14618",

language = "English",

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AU - Kim, Youngmi

AU - Kim, Hyuna

AU - Park, Deokbum

AU - Lee, Hansoo

AU - Lee, Yun Sil

AU - Choe, Jongseon

AU - Kim, Young Myeong

AU - Jeon, Doyong

AU - Jeoung, Dooil

N1 - Funding 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).

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Anti-cancer drug-resistance

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KW - GSK3β

KW - Peptides

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DO - 10.18632/oncotarget.14618

M3 - Article

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SN - 1949-2553

VL - 8

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EP - 13619

JO - Oncotarget

JF - Oncotarget

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ER -

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

Bibliographical note

Keywords

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