title: Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yu Ri
authors.initials: YR
authors.lastname: Jung
authors.affiliation: 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.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Hyeong Jwa
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Hak-Su
authors.initials: HS
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.affiliation: 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 mylee@kcch.re.kr.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001241:Aspirin / Q000008:administration & dosage / Q000378:metabolism*; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D045325:HCT116 Cells; D006801:Humans; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D001241:Aspirin