AMPK-mediated up-regulation of mTORC2 and MCL-1 compromises the anti-cancer effects of aspirin.
AMPK-mediated up-regulation of mTORC2 and MCL-1 compromises the anti-cancer effects of aspirin.
复制标题
AMPK 介导的 mTORC2 和 MCL-1 上调会损害阿司匹林的抗癌作用。
DOI：
10.18632/oncotarget.7648
复制
发表时间：
2016-03-29
期刊：
影响因子：
--
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Gao M;Kong Q;Hua H;Yin Y;Wang J;Luo T;Jiang Y
AMP活化蛋白激酶（AMPK）是一种重要的能量传感器，可抑制细胞增殖或促进细胞在应激过程中的存活。除了环氧合酶，AMPK是非类固醇抗炎药阿司匹林的另一个靶点。临床前和临床研究表明，阿司匹林可以抑制几种类型的癌症，如结直肠腺瘤和肝细胞癌（HCC）。然而，对阿司匹林的细胞反应可能导致阿司匹林抵抗知之甚少。我们发现阿司匹林通过AMPK-mTOR-Akt/ERK轴诱导HepG 2和SW 480细胞中MCL-1的表达。用阿司匹林处理HepG 2和SW 480细胞导致MCL-1表达、Akt和ERK 1/2磷酸化增加。Akt/MEK的抑制消除了阿司匹林对MCL-1的诱导。阿司匹林激活AMPK，进而上调mTORC 2活性、Akt、ERK 1/2磷酸化和MCL-1表达。MCL-1敲低使癌细胞对阿司匹林诱导的凋亡敏感。阿司匹林与AMPK、Akt或MEK抑制剂联合应用比单独应用更能显著抑制细胞增殖和诱导细胞凋亡。此外，索拉非尼阻断阿司匹林诱导的MCL-1上调。阿司匹林和索拉非尼的组合比单独使用每种药物导致更多的细胞死亡和更少的细胞增殖。用阿司匹林和索拉非尼两者治疗HCC和结肠癌异种移植物比单一药剂导致更显著的肿瘤抑制。这些数据表明，AMPK介导的mTORC 2和MCL-1的上调可能会损害阿司匹林的抗癌作用。阿司匹林联合索拉非尼可能是治疗肝癌和结肠癌的有效方案。
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.