title: Benzo[a]pyrene-induced cell cycle progression occurs via ERK-induced Chk1 pathway activation in human lung cancer cells.
abstract: Benzo[a]pyrene (B[a]P) is a potent lung carcinogen derived from tobacco smoking and environmental contamination. This study aimed to investigate the signal transduction pathway responsible for B[a]P-induced non-small cell lung cancer (NSCLC) development. We exposed the human NSCLC cell lines Calu-1, CL3, H1299, CH27, H23, and H1355 to B[a]P and assessed cell cycle progression using flow cytometry. Expression of cell cycle mediators was measured using Western blot analyses and electrophoretic mobility shift assays (EMSAs). B[a]P exposure dramatically induced S-phase accumulation in H1355 cells. Phospho-p53 (Ser15 and Ser20), phospho-ERK, phospho-p38, and Bax were significantly increased in H1355 cells whereas phospho-Rb was decreased in these cells. In addition, B[a]P induced phosphorylation of checkpoint kinase-1 (Chk1) but not Chk2. EMSA experiments revealed a slower migrating band after c-Myc bound the E-box in response to B[a]P treatment, which was abolished upon the addition of the ERK inhibitor PD98059 in H1355 cells. Phospho-ERK inhibition and dominant negative mutant Chk1 expression reversed B[a]P-induced S phase accumulation and downregulated phospho-Chk1 and phospho-ERK expression. Taken together, these results suggest that activation of ERK and its downstream mediator Chk1 may contribute to B[a]P-induced S phase accumulation in H1355 cells. The results could help in the development of lung cancer treatments that target the Chk1 pathway through ERK.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Taiwan.
authors.forename: Bing-Yen
authors.initials: BY
authors.lastname: Wang
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Sung-Yu
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan; Division of Chinese Medicine, Department of Health, Executive Yuan, Hualien Hospital, Taiwan.
authors.forename: Sheau-Chung
authors.initials: SC
authors.lastname: Tang
authors.affiliation: Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan; Division of Chinese Medicine, Department of Health, Executive Yuan, Hualien Hospital, Taiwan.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Lai
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chu-Chyn
authors.initials: CC
authors.lastname: Ou
authors.affiliation: Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Wu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan. Electronic address: ymhsiao@ctust.edu.tw.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Hsiao
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taiwan. Electronic address: jlko@csmu.edu.tw.
authors.forename: Jiunn-Liang
authors.initials: JL
authors.lastname: Ko
mesh_terms: D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001564:Benzo(a)pyrene; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Benzo[a]pyrene; Chk1; ERK; P-p53; S phase accumulation