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.

Chang J, Xue M, Yang S, Yao B, Zhang B, Chen X, Pozzi A, Zhang MZ
PLoS One. 2015 10 (5): e0127030

PMID: 26011146 · PMCID: PMC4444260 · DOI:10.1371/journal.pone.0127030

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.

MeSH Terms (19)

11-beta-Hydroxysteroid Dehydrogenases Animals Apoptosis Carcinogenesis Cell Line, Tumor Cell Proliferation Corticosterone Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Endoplasmic Reticulum Stress Extracellular Signal-Regulated MAP Kinases Glycyrrhetinic Acid Humans Lung Neoplasms Male Mice, Inbred C57BL Models, Biological Signal Transduction TOR Serine-Threonine Kinases

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