title: Inhibition of 11β-Hydroxysteroid Dehydrogenase Type II Suppresses Lung Carcinogenesis by Blocking Tumor COX-2 Expression as Well as the ERK and mTOR Signaling Pathways.
abstract: Lung cancer is by far the leading cause of cancer death. Early diagnosis and prevention remain the best approach to reduce the overall morbidity and mortality. Experimental and clinical evidence have shown that cyclooxygenase-2 (COX-2) derived prostaglandin E2 (PGE2) contributes to lung tumorigenesis. COX-2 inhibitors suppress the development and progression of lung cancer. However, increased cardiovascular risks of COX-2 inhibitors limit their use in chemoprevention of lung cancers. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are down-regulated by 11β-hydroxysteroid dehydrogenase type II (11ßHSD2)-mediated metabolism. We found that 11βHSD2 expression was increased in human lung cancers and experimental lung tumors. Inhibition of 11βHSD2 activity enhanced glucocorticoid-mediated COX-2 inhibition in human lung carcinoma cells. Furthermore, 11βHSD2 inhibition suppressed lung tumor growth and invasion in association with increased tissue active glucocorticoid levels, decreased COX-2 expression, inhibition of ERK and mTOR signaling pathways, increased tumor endoplasmic reticulum stress as well as increased lifespan. Therefore, 11βHSD2 inhibition represents a novel approach for lung cancer chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity and/or inhibits the ERK and mTOR signaling pathways.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Shilin
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Bixiang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States of America; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States of America; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003345:Corticosterone / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006034:Glycyrrhetinic Acid; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D042842:11-beta-Hydroxysteroid Dehydrogenases; D051546:Cyclooxygenase 2; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D006034:Glycyrrhetinic Acid; D003345:Corticosterone