title: Involvement of creatine kinase B in cigarette smoke-induced bronchial epithelial cell senescence.
abstract: Cigarette smoke induces damage to proteins and organelles by oxidative stress, resulting in accelerated epithelial cell senescence in the lung, which is implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Although the detailed molecular mechanisms are not fully understood, cellular energy status is one of the most crucial determinants for cell senescence. Creatine kinase (CK) is a constitutive enzyme, playing regulatory roles in energy homeostasis of cells. Among two isozymes, brain-type CK (CKB) is the predominant CK in lung tissue. In this study, we investigated the role of CKB in cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBECs). Primary HBECs and Beas2B cells were used. Protein carbonylation was evaluated as a marker of oxidative protein damage. Cellular senescence was evaluated by senescence-associated β-galactosidase staining. CKB inhibition was examined by small interfering RNA and cyclocreatine. Secretion of IL-8, a hallmark of senescence-associated secretary phenotype, was measured by ELISA. CKB expression levels were reduced in HBECs from patients with COPD compared with that of HBECs from nonsmokers. CSE induced carbonylation of CKB and subsequently decreased CKB protein levels, which was reversed by a proteasome inhibitor. CKB inhibition alone induced cell senescence, and further enhanced CSE-induced cell senescence and IL-8 secretion. CSE-induced oxidation of CKB is a trigger for proteasomal degradation. Concomitant loss of enzymatic activity regulating energy homeostasis may lead to the acceleration of bronchial epithelial cell senescence, which is implicated in the pathogenesis of COPD.
authors: Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
authors: Hiromichi
authors: H
authors: Hara
authors: Jun
authors: J
authors: Araya
authors: Naoki
authors: N
authors: Takasaka
authors: Satoko
authors: S
authors: Fujii
authors: Jun
authors: J
authors: Kojima
authors: Yoko
authors: Y
authors: Yumino
authors: Kenichiro
authors: K
authors: Shimizu
authors: Takeo
authors: T
authors: Ishikawa
authors: Takanori
authors: T
authors: Numata
authors: Makoto
authors: M
authors: Kawaishi
authors: Keisuke
authors: K
authors: Saito
authors: Jun
authors: J
authors: Hirano
authors: Makoto
authors: M
authors: Odaka
authors: Toshiaki
authors: T
authors: Morikawa
authors: Hiroshi
authors: H
authors: Hano
authors: Katsutoshi
authors: K
authors: Nakayama
authors: Kazuyoshi
authors: K
authors: Kuwano
mesh_terms: D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D052276:Creatine Kinase, BB Form / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056744:Cyclin B1 / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D050050:Protein Carbonylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D054875:Ubiquitination; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C534699:CCNB1 protein, human; C508606:CXCL8 protein, human; D056744:Cyclin B1; D016209:Interleukin-8; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D012906:Smoke; D052276:Creatine Kinase, BB Form; D001616:beta-Galactosidase; D046988:Proteasome Endopeptidase Complex