PPARalpha and PPARbeta are differentially affected by ethanol and the ethanol metabolite acetaldehyde in the MCF-7 breast cancer cell line.
The activity and/or the level of the peroxisome proliferator-activated receptors (PPARs) in liver and oligodendrocytes are regulated by ethanol. Despite the association between ethanol consumption and breast cancer risk, and the increasing evidence for an involvement of PPARs in some cancers, there have been no studies on the effect of ethanol or its metabolite acetaldehyde on PPARs in breast cancer. Using the MCF-7 breast cancer cell line, we examined the relationship between ethanol and its metabolite acetaldehyde on PPARalpha and PPARbeta transactivation. Ethanol (20 mM) reduced the potency of the PPARbeta ligand GW0742, evident by a rightward shift in the GW0742 dose-response curve, whereas for PPARalpha activation by GW7647, ethanol mediated its effects primarily through reducing efficacy as evidenced by a reduction in maximal response. Using the enzyme inhibitors 4-methylpyrazole and cyanamide and the metabolite acetaldehyde, we showed that PPARalpha and PPARbeta are differentially modulated by ethanol and acetaldehyde. While acetaldehyde is responsible for the inhibition of PPARalpha ligand inhibition with a concentration that inhibits 50% of activity (IC50) of 111 nM, acetaldehyde has no effect on PPARbeta or its ligand activation. Instead, inhibition of PPARbeta transactivation is mediated directly by ethanol. The differential effect of ethanol and acetaldehyde on PPARalpha and PPARbeta further underscores the differences between these receptors and may indicate the relevance of PPARs in the effects of ethanol in the human breast.
Venkata
Nagaraj Gopisetty
NG
School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072, Australia.
Aung
Cho S
CS
Cabot
Peter J
PJ
Monteith
Gregory R
GR
Roberts-Thomson
Sarah J
SJ
D000079:Acetaldehyde / Q000378:metabolism / Q000633:toxicity*; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001943:Breast Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003484:Cyanamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D000077604:Fomepizole; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D047493:PPAR alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D010636:Phenols; D013438:Sulfhydryl Compounds
D000079:Acetaldehyde; D000426:Alcohol Dehydrogenase; D000445:Aldehyde Oxidoreductases; D003484:Cyanamide; D004791:Enzyme Inhibitors; D000431:Ethanol; D000077604:Fomepizole; D047493:PPAR alpha; D048068:PPAR-beta; D011720:Pyrazoles; D012333:RNA, Messenger; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C018699:aldehyde dehydrogenase (NAD(P)+)