Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling.
Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling.
复制标题
DOI：
10.1158/0008-5472.can-16-2400
复制
发表时间：
2017-02-01
期刊：
影响因子：
11.2
通讯作者：
Toker A
中科院分区：
文献类型：
--
作者：
Henry WS;Laszewski T;Tsang T;Beca F;Beck AH;McAllister SS;Toker A
尽管编码磷脂酰肌醇3-激酶(PI3K)催化亚单位(PI3K)的基因PIK3CA的致癌突变发生率很高，但PI3K抑制剂对乳腺癌患者的临床益处很小。最近的流行病学研究表明，服用阿司匹林对携带致癌PIK3CA的癌症患者有治疗益处。在这里，我们显示表达突变的PIK3CA的乳腺癌细胞对阿司匹林介导的生长抑制比它们的野生型对应细胞具有更高的敏感性。阿司匹林降低突变型PIK3CA乳腺癌细胞的活力和非锚定生长，其作用不依赖于其对环氧合酶-2(COX-2)和核因子-kappaB(NF-κB)的影响。我们将阿司匹林的作用归因于AMP激活蛋白激酶(AMPK)的激活、哺乳动物雷帕霉素复合体靶标1(MTORC1)的抑制以及自噬的诱导。在体内，每天用阿司匹林治疗致癌的PIK3CA驱动的小鼠乳腺肿瘤导致肿瘤生长动力学下降，而阿司匹林和PI3K抑制剂的联合治疗进一步减弱了肿瘤的生长。我们的研究支持评价阿司匹林和PI3K途径抑制剂作为靶向乳腺癌的联合治疗。
Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiological studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA. Here we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-κB). We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mammalian target of rapamycin complex 1 (mTORC1) inhibition, and autophagy induction. In vivo, oncogenic PIK3CA-driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, while combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports evaluation of aspirin and PI3K pathway inhibitors as combination therapy for targeting breast cancer.