GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth.

Oncotarget
Junghui KooShi-Yong Sun

Abstract

The single-agent activity of rapalogs (rapamycin and its analogues) in most tumor types has been modest at best. The underlying mechanisms are largely unclear. In this report, we have uncovered a critical role of GSK3 in regulating degradation of some oncogenic proteins induced by rapalogs and cell sensitivity to rapalogs. The basal level of GSK3 activity was positively correlated with cell sensitivity of lung cancer cell lines to rapalogs. GSK3 inhibition antagonized rapamycin's growth inhibitory effects both in vitro and in vivo, while enforced activation of GSK3β sensitized cells to rapamycin. GSK3 inhibition rescued rapamcyin-induced reduction of several oncogenic proteins such as cyclin D1, Mcl-1 and c-Myc, without interfering with the ability of rapamycin to suppress mTORC1 signaling and cap binding. Interestingly, rapamycin induces proteasomal degradation of these oncogenic proteins, as evidenced by their decreased stabilities induced by rapamcyin and rescue of their reduction by proteasomal inhibition. Moreover, acute or short-time rapamycin treatment dissociated not only raptor, but also rictor from mTOR in several tested cell lines, suggesting inhibition of both mTORC1 and mTORC2. Thus, induction of GSK3-dependent deg...Continue Reading

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Citations

Sep 8, 2019·Proceedings of the National Academy of Sciences of the United States of America·Long HeJohn Blenis
Mar 1, 2018·Molecular Medicine Reports·Jianxiang SongShiying Zheng
Feb 27, 2016·Molecular Cancer Therapeutics·Suman MukhopadhyayDavid A Foster
Sep 4, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yong LinYan Zhang
Dec 31, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Camilla EvangelistiAlberto M Martelli

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Methods Mentioned

BETA
flow cytometry
xenografts
xenograft
gene knockdown
transfection
pull-down
reverse transcription-PCR
immunoprecipitation

Software Mentioned

GraphPad InStat
NIH Image J
CompuSyn
GraphPad

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