beta-Carotene and cigarette smoke condensate regulate heme oxygenase-1 and its repressor factor Bach1: relationship with cell growth.
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.
Palozza
Paola
P
Institute of General Pathology, Catholic University School of Medicine, Rome, Italy. p.palozza@rm.unicatt.it
Serini
Simona
S
Currò
Diego
D
Calviello
Gabriella
G
Igarashi
Kazuhiko
K
Mancuso
Cesare
C
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D011524:Protoporphyrins / Q000378:metabolism; D051381:Rats; D012906:Smoke; D014026:Nicotiana / Q000737:chemistry*; D014815:Vitamins / Q000378:metabolism*; D019207:beta Carotene / Q000378:metabolism*
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D011524:Protoporphyrins; D012906:Smoke; D014815:Vitamins; D019207:beta Carotene; D002248:Carbon Monoxide; C028025:protoporphyrin IX; D051547:Heme Oxygenase-1; D001663:Bilirubin