Upregulation of CMO1 as possible link between β‐carotene supplementation and increased risk of lung cancer

Abstract

In several large clinical trials, administration of high doses of β‐carotene has been associated with increased lung cancer risk in chronic smokers. The mechanism for this association remains unknown. We hypothesized that regulation of β‐carotene 15,15′‐monooxygenase (CMO1) expression may be a potential mechanism for supra‐physiologic β‐carotene dosing and increased lung cancer risk. We demonstrate that human alveolar epithelial (A549) cells robustly express CMO1 and metabolize β‐carotene to several biologically active retinoic acid isomers. Exposure of A549 cells to β‐carotene initially (<6 h) induces, and then suppresses cellular CMO1 mRNA and protein levels. β‐carotene suppresses CMO1 promoter activity in a dosage‐dependent manner. Treatment with supra‐physiologic levels of b‐carotene decreases cellular levels of PPARγ and reduces formation of functional PPARγ/RXRa heterodimers, resulting in inhibition of CMO1 promoter activity. We also show that β‐carotene treatment antagonizes PPARγ activity in HEK293 cells that stably express CMO1, but not in cells that express the mutant (non‐enzymatic) CMO1. Immunohistochemical analysis of non‐small cell lung carcinomas shows greater CMO1 staining than in adjacent normal lung, which is consistent with an increased expression of PPARγ in lung carcinogenesis. These findings suggest that β‐carotene suppresses CMO1 gene expression through downregulation of PPARγ in alveolar epithelial cells. Increased CMO1 expression in lung cancer may lead to accumulation of retinaldehyde from cleavage of β‐carotene and inhibition of PPARγ which, in turn, promotes carcinogenesis. This pathway may explain adverse effects of supra‐physiologic b‐carotene supplementation in lung cancer trials. (NIH HD42174, Muma Family Endowment)