HMG-CoA reductase and PPARalpha are involved in clofibrate-induced apoptosis in human keratinocytes.
Contrasting data have been reported on the effects of clofibrate, a PPARalpha agonist and hypolipidemic drug. The carcinogenic and anti-apoptotic effects have been demonstrated especially in rodents in both "in vivo" and "in vitro" experiments. In contrast, in rat and human hepatoma cell lines, several reports have shown its concentration-dependent pro-apoptotic effect. No epidemiological data exist about its carcinogenetic effect in man. This study shows that clofibrate also induced apoptosis in a human non-tumour cell line, NCTC 2544, which shares the characteristic of proliferation with tumour cells. Both HMG-CoA reductase and PPARalpha were found to be involved in the signal transduction pathway inducing apoptosis, the former being the principal target: HMG-CoA reductase decreased and PPARalpha increased. Changes in HMG-CoA reductase expression caused activation of parameters leading to apoptosis via the mitochondria pathway. Clofibrate must be considered a pro-apoptotic molecule at concentrations of 0.25 mM and above: the effect is exercised not only on tumour cells but also on normal human proliferating cells. Clofibrate should thus be regarded as a potential drug to reduce the number of proliferating cells in pathological conditions.
Muzio
G
G
Department of Experimental Oncology and Medicine, Turin University, Corso Raffaello 30, 10125, Turin, Italy.
Martinasso
G
G
Trombetta
A
A
Di Simone
D
D
Canuto
R A
RA
Maggiora
M
M
D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002994:Clofibrate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008954:Models, Biological; D047493:PPAR alpha / Q000378:metabolism*
D047493:PPAR alpha; D006903:Hydroxymethylglutaryl CoA Reductases; D002994:Clofibrate