beta-Carotene and cigarette smoke condensate regulate heme oxygenase-1 and its repressor factor Bach1: relationship with cell growth

Antioxid Redox Signal. May-Jun 2006;8(5-6):1069-80. doi: 10.1089/ars.2006.8.1069.

Abstract

It has been reported that beta-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 beta-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 microg/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 beta-carotene (1 microM) 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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Bilirubin / metabolism
  • Carbon Monoxide / metabolism
  • Cell Cycle / physiology
  • Cell Line
  • Fanconi Anemia Complementation Group Proteins / genetics
  • Fanconi Anemia Complementation Group Proteins / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation, Enzymologic*
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Protoporphyrins / metabolism
  • Rats
  • Smoke*
  • Tobacco / chemistry*
  • Vitamins / metabolism*
  • beta Carotene / metabolism*

Substances

  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • Fanconi Anemia Complementation Group Proteins
  • Protoporphyrins
  • Smoke
  • Vitamins
  • beta Carotene
  • Carbon Monoxide
  • protoporphyrin IX
  • Heme Oxygenase-1
  • Bilirubin