Mechanism of Activation of AMPK and Upregulation of OGG1 by Rapamycin in Cancer Cells

AMPK is a physiological cellular energy sensor that is activated by phosphorylation at Thr172 in response to changes in cellular ATP levels. AMPK has been recognized as an important upstream signaling intermediate intimately involved in the regulation of the mTOR pathway [1]. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. In addition, AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell cycle arrest induced by energy stress. Recent studies show that raptor was identified as a direct substrate of the AMPK. AMPK phosphorylates raptor on Ser722/Ser792 which it is essential for inhibition of the raptor-containing mTOR complex I (mTORCI). Moreover, AMPK is activated by the adenosine analogue, 5-aminoimidazole-4-carboxamide (AICA)-riboside (AICAR) and metformin. These drugs have been used to inhibit the growth and survival of breast cancer and glioblastomas cells [2]. mTOR is a large protein kinase with two different complexes. One complex contains mTOR, GβL and raptor, which is a target of rapamycin [3]. The other complex, insensitive to rapamycin, includes mTOR, GβL, Sin1, and rictor. The mTOR-rictor complex phosphorylates Ser473 of Akt/PKB, which is essential for full Akt/PKB activation. We have evidence in TSC-deficient proximal tubular cells accumulates significant amounts of ROS compared to wild type cells (data not shown). Accumulation of ROS is associated with activation/phosphorylation of Akt at Ser473, inactivation/phosphorylation of tuberin at Thr1462 and activation mTOR/rictor complex II [3]. In addition, Akt can be activated through the feedback mechanism of mTOR-rictor complex activation. Additional evidence indicates that rictor is phosphorylated at Thr1135 by p70S6K, which negatively regulates mTORC2 protein complex as part of a negative feedback mechanism controlling Akt activity [4]. Targeting mTOR is emerging as an important approach in cancer therapeutics [3]. Early clinical trials