β-Carotene and Cigarette Smoke Condensate Regulate Heme Oxygenase-1 and Its Repressor Factor Bach1: Relationship with Cell Growth

It has been reported that β-carotene is able to increase lung cancer risk in chronic smokers, but the mechanism for this association remains unknown. This article reports the first evidence that β-carotene, combined with cigarette smoke condensate (TAR), regulates heme oxygenase-1 (HO-1) via its transcriptional factor Bach1 and modulates cell growth. Both immortalized rat fibroblasts (RAT-1) and human lung cancer cells(Mv1Lu) exposed to TAR (25 µg/ml), exhibited an initial (6 h) induction of HO-1, followed by a late (24 h) repression due to the activation of Bach1. Heme oxygenase-1 repression was much more consistent when TAR was administered in combination with β-carotene (1 µM) for 24 h; at this concentration the carotenoid per se did not have any effect on HO-1. Interestingly, the HO-1 repression following TAR plus β-carotene treatment caused a resynchronization of RAT-1 cell-cycle with a significant increase in the S-phase, and this was probably due to the decreased intracellular levels of carbon monoxide and bilirubin, both of which have antiproliferative effects. The role of HO-1 repression in increasing cell growth was also confirmed in Mv1Lu cells by the"knock down" of the Bach1 gene, thus demonstrating as HO-1 repression is a conserved mechanism by which cells can react to oxidative stress.