Jung Yu Ri, Kim Eun Ju, Choi Hyeong Jwa, Park Jung-Jin, Kim Hak-Su, Lee Yoon-Jin, Park Myung-Jin, Lee Minyoung
Division of Radiation Effect (Y.R.J., E.J.K., H.J.C., Y.-J.L., M.L.), Division of Radiation Cancer Research (M.-J.P.), Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; Department of Biochemistry and Medical Research Center (J.-J.P.), College of Medicine, Chungbuk National University, Cheongju, Republic of Korea; and Department of Pharmacology and Hypoxia-Related Diseases Research Center (H.-S.K.), College of Medicine, Inha University, Incheon, Republic of Korea.
Division of Radiation Effect (Y.R.J., E.J.K., H.J.C., Y.-J.L., M.L.), Division of Radiation Cancer Research (M.-J.P.), Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; Department of Biochemistry and Medical Research Center (J.-J.P.), College of Medicine, Chungbuk National University, Cheongju, Republic of Korea; and Department of Pharmacology and Hypoxia-Related Diseases Research Center (H.-S.K.), College of Medicine, Inha University, Incheon, Republic of Korea
Mol Pharmacol. 2015 Oct;88(4):708-19. doi: 10.1124/mol.115.098616. Epub 2015 Jul 28.
Cancer therapies attempt to destroy the entire tumor, but this tends to require toxic compounds and high doses of radiation. Recently, considerable attention has focused on therapy-induced senescence (TIS), which can be induced in cancer cells by low doses of therapeutic drugs or radiation and provides a barrier to tumor development. However, the molecular mechanisms governing TIS remain elusive. Special attention has been paid to the potential chemopreventive effect of aspirin against human colorectal cancer. In this study, we investigated the effects of aspirin on TIS of human colorectal carcinoma (CRC) cells and show that it occurs via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), two key regulators of cellular metabolism. Aspirin increased the senescence of CRC cells, increased the protein levels of SIRT1, phospho-AMPK (T172), and phospho-acetyl CoA carboxylase (S79), and reduced the cellular level of ATP. Small-interfering RNA-mediated downregulation or pharmacological inhibition of SIRT1 or AMPK significantly attenuated the aspirin-induced cellular senescence in CRC cells. In contrast, treatment with a SIRT1 agonist or an AMP analog induced cellular senescence. Remarkably, SIRT1 knockdown abrogated the aspirin-induced activation of AMPK, and vice versa. During the progression of aspirin-induced cellular senescence in CRC cells, SIRT1 showed increased deacetylase activity at a relatively early time point but was characterized by decreased activity with increased cytoplasmic localization at a later time point. Collectively, these novel findings suggest that aspirin could provide anticancer effects by inducing senescence in human CRC cells through the reciprocal regulation of SIRT1-AMPK pathways.
癌症治疗旨在摧毁整个肿瘤，但这往往需要使用有毒化合物和高剂量辐射。最近，治疗诱导的衰老（TIS）受到了广泛关注，低剂量的治疗药物或辐射可在癌细胞中诱导TIS，从而为肿瘤发展提供障碍。然而，控制TIS的分子机制仍不清楚。阿司匹林对人类结直肠癌的潜在化学预防作用受到了特别关注。在本研究中，我们研究了阿司匹林对人结肠癌细胞TIS的影响，结果表明其通过细胞代谢的两个关键调节因子——沉默调节蛋白1（SIRT1）和AMP激活的蛋白激酶（AMPK）发挥作用。阿司匹林增加了结肠癌细胞的衰老，提高了SIRT1、磷酸化AMPK（T172）和磷酸化乙酰辅酶A羧化酶（S79）的蛋白水平，并降低了细胞内ATP水平。小干扰RNA介导的SIRT1或AMPK下调或药理学抑制显著减弱了阿司匹林诱导的结肠癌细胞衰老。相反，用SIRT1激动剂或AMP类似物处理可诱导细胞衰老。值得注意的是，敲低SIRT1可消除阿司匹林诱导的AMPK激活，反之亦然。在阿司匹林诱导的结肠癌细胞衰老过程中，SIRT1在相对早期显示出增加的去乙酰化酶活性，但在后期表现为活性降低且细胞质定位增加。总的来说，这些新发现表明阿司匹林可通过SIRT1-AMPK途径的相互调节诱导人结肠癌细胞衰老，从而发挥抗癌作用。
