Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways.
Numerous studies have shown that mammalian target of rapamycin (mTOR) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling. In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin-mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors. Moreover, we analyzed the effect of mTORC1 and mTORC2 on regulating cell cycle progression. We found that low concentrations rapamycin increased Akt and ERK phosphorylation through a mTORC1-dependent mechanism because knockdowned raptor induced the activation of Akt and ERK, but higher doses of rapamycin inhibited Akt and ERK phosphorylation mainly via the mTORC2 signaling pathway because that the silencing of rictor led to the inhibition of Akt and ERK phosphorylation. We further showed that mTORC2 was tightly associated with the development of cell cycle through an Akt-dependent mechanism. Therefore, we combined PI3K and ERK inhibitors prevent rapamycin-induced Akt activation and enhanced antitumor effects of rapamycin. Collectively, we conclude that mTORC2 plays a much more important role than mTORC1 in rapamycin-mediated phosphorylation of Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin-based therapeutic approaches in cancer cells.
Chen
Xian-Guo
XG
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
Liu
Fei
F
Song
Xing-Fu
XF
Wang
Zhi-Hua
ZH
Dong
Zi-Qiang
ZQ
Hu
Zhi-Quan
ZQ
Lan
Ru-Zhu
RZ
Guan
Wei
W
Zhou
Tian-Gui
TG
Xu
Xiao-Ming
XM
Lei
Hong
H
Ye
Zhang-Qun
ZQ
Peng
E-Jun
EJ
Du
Li-Huan
LH
Zhuang
Qian-Yuan
QY
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; C493245:CRTC2 protein, human; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus