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.