GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth.
GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth.
复制标题
DOI：
10.18632/oncotarget.3291
复制
发表时间：
2015-04-20
期刊：
影响因子：
--
通讯作者：
Sun SY
中科院分区：
文献类型：
--
作者：
Koo J;Wang X;Owonikoko TK;Ramalingam SS;Khuri FR;Sun SY
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 degradation of these oncogenic proteins is likely secondary to mTORC2 inhibition; this effect should be critical for rapamycin to exert its anticancer activity.
登录
查看更多内容
影响因子：
4.8
作者：
Mills CN;Nowsheen S;Bonner JA;Yang ES
通讯作者：
Yang ES
影响因子：
16
作者：
Lin, Douglas I.;Barbash, Olena;Diehl, J. Alan
通讯作者：
Diehl, J. Alan
影响因子：
120.1
作者：
Cohen, P;Goedert, M
通讯作者：
Goedert, M
细胞周期蛋白D1降解的调节：在癌症发展中的作用和治疗发明的潜力。
影响因子：
37.3
作者：
Alao, John P.
通讯作者：
Alao, John P.
影响因子：
8.2
作者：
Barlow, A. D.;Xie, J.;Moore, C. E.;Campbell, S. C.;Shaw, J. A. M.;Nicholson, M. L.;Herbert, T. P.
通讯作者：
Herbert, T. P.