AMPK-mediated up-regulation of mTORC2 and MCL-1 compromises the anti-cancer effects of aspirin

// Mei Gao 1, * , Qingbin Kong 1, * , Hui Hua 2 , Yancun Yin 3 , Jiao Wang 4 , Ting Luo 5 , Yangfu Jiang 1 1 State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, China 2 Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, China 3 Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, China 4 School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China 5 Cancer Center, West China Hospital, Chengdu, China * These authors contributed equally to this work Correspondence to: Yangfu Jiang, e-mail: jyangfu@scu.edu.cn Keywords: aspirin, drug resistance, experimental cancer therapy, AMP-activated protein kinase, MCL-1 Abbreviations: AMPK, AMP-activated protein kinase, mTORC2, mTOR complex 2 Received: August 20, 2015      Accepted: February 06, 2016      Published: February 23, 2016 ABSTRACT AMP-activated protein kinase (AMPK) is an important energy sensor that may inhibit cell proliferation or promote cell survival during stresses. Besides cyclooxygenase, AMPK is another target of the nonsteroid anti-inflammatory agent aspirin. Preclinical and clinical investigations demonstrate that aspirin can inhibit several types of cancer such as colorectal adenomas and hepatocellular carcinoma (HCC). However, little is known about the cellular response to aspirin that may lead to aspirin resistance. Here, we show that aspirin induces the expression of MCL-1 in HepG2 and SW480 cells through AMPK-mTOR-Akt/ERK axis. Treatment of HepG2 and SW480 cells with aspirin leads to increased MCL-1 expression, Akt and ERK1/2 phosphorylation. Inhibition of Akt/MEK abrogates the induction of MCL-1 by aspirin. Aspirin activates AMPK, which in turn up-regulates mTORC2 activity, Akt, ERK1/2 phosphorylation and MCL-1 expression. MCL-1 knockdown sensitizes cancer cells to aspirin-induced apoptosis. Combination of aspirin and AMPK, Akt or MEK inhibitor results in more significant inhibition of cell proliferation and induction of apoptosis than single agent. Moreover, sorafenib blocks aspirin-induced MCL-1 up-regulation. Combination of aspirin and sorafenib leads to much more cell death and less cell proliferation than each drug alone. Treatment of HCC and colon cancer xenografts with both aspirin and sorafenib results in more significant tumor suppression than single agent. These data demonstrate that AMPK-mediated up-regulation of mTORC2 and MCL-1 may compromise the anticancer effects of aspirin. Combination of aspirin and sorafenib may be an effective regimen to treat HCC and colon cancer.