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.
Highlights
Lung cancer is the second most common cancer in both men and women and is by far the leading cause of cancer death among both men and women
To investigate whether 11ßHSD2 might be involved in lung tumorigenesis, its expression in normal mouse lung tissue, experimental lung cancer, normal human lung tissue and different human lung cancers was investigated with immunohistochemistry
In athymic nude mouse lung tissue, 11ßHSD2 was expressed in the epithelial cells of small airways and alveoli (Fig 1A). 11ßHSD2 expression was increased in A549 adenocarcinoma compared to adjacent normal athymic nude mouse lung tissue (Fig 1B). 11ßHSD2 immunostaining was strong in human adenocarcinoma and squamous cell carcinoma, moderate in papillary carcinoma as well as small cell lung cancer, but very weak in normal human lung tissue (Fig 1C)
Summary
Lung cancer is the second most common cancer in both men and women and is by far the leading cause of cancer death among both men and women. Most patients present with advanced, non-curable disease. There are only 15% of patients still alive 5 years after diagnosis [1,2]. Early diagnosis and prevention remain the best approach to reduce the overall morbidity and mortality of lung cancer. There are two major types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 85%-90% of lung cancers and contains three main subtypes: squamous cell (epidermoid) carcinoma, adenocarcinoma and large cell (undifferentiated) carcinoma
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