title: Chronic Stress Facilitates Lung Tumorigenesis by Promoting Exocytosis of IGF2 in Lung Epithelial Cells.
abstract: Molecular insights into how chronic stress affects lung tumorigenesis may offer new routes to chemoprevention. In this study, we show that chronic stress in mice chemically or genetically initiated for lung cancer leads to the release of norepinephrine and other catecholamines, thereby promoting lung tumorigenesis. Mechanistically, norepinephrine induced phosphorylation of L-type voltage-dependent calcium channels (VDCC) through the β-adrenergic receptor-PKA pathway. VDCC triggered calcium mobilization, thereby inducing activation of IGF-1R via exocytosis of insulin-like growth factor 2 (IGF2). Mice expressing lung-specific IGF-1R exhibited accelerated lung tumor development in response to chronic stress. Notably, clinically approved antihypertensive drugs that block L-type VDCC prevented the effects of chronic stress or norepinephrine on the IGF2/IGF-1R signaling cascade, along with transformation of lung epithelial cells and lung tumor formation. Overall, our results identify an actionable mechanism to limit the effects of chronic stress on lung tumorigenesis. Cancer Res; 76(22); 6607-19. ©2016 AACR.
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Boo
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ho Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Gyeonggi, Republic of Korea.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, Republic of Korea. hylee135@snu.ac.kr.|Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Gyeonggi, Republic of Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D049109:Cell Proliferation; D005089:Exocytosis; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D015398:Signal Transduction; D013315:Stress, Psychological / Q000150:complications*; D014162:Transfection
chemical_list: C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II