title: Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence.
abstract: Cigarette smoke (CS)-induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.
authors.affiliation: Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan;
authors.forename: Naoki
authors.initials: N
authors.lastname: Takasaka
authors.forename: Jun
authors.initials: J
authors.lastname: Araya
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hara
authors.forename: Saburo
authors.initials: S
authors.lastname: Ito
authors.forename: Kenji
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kurita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakui
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshii
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yumino
authors.forename: Satoko
authors.initials: S
authors.lastname: Fujii
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Minagawa
authors.forename: Chikako
authors.initials: C
authors.lastname: Tsurushige
authors.forename: Jun
authors.initials: J
authors.lastname: Kojima
authors.forename: Takanori
authors.initials: T
authors.lastname: Numata
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Shimizu
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawaishi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Noriki
authors.initials: N
authors.lastname: Kamiya
authors.forename: Jun
authors.initials: J
authors.lastname: Hirano
authors.forename: Makoto
authors.initials: M
authors.lastname: Odaka
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Morikawa
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kuwano
mesh_terms: D000107:Acetylation; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D001980:Bronchi / Q000473:pathology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005541:Forced Expiratory Volume; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000502:physiology; D009154:Mutation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology* / Q000503:physiopathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014026:Nicotiana; D014797:Vital Capacity
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D012906:Smoke; D007334:Insulin-Like Growth Factor I; C546842:MTOR protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C516592:SIRT6 protein, human; D037761:Sirtuins