Apoptosis induced by clofibrate in Yoshida AH-130 hepatoma cells: Role of HMG-CoA reductase

Rosa A. Canuto, Giuliana Muzio, Marina Maggiora, Antonella Trombetta, Germana Martinasso, Riccardo Autelli, Paola Costelli, Gabriella Bonelli, and Francesco M. Baccino

Medicina Oncologia Sperimentale, University of Turin, Turin 10125

Corresponding Author: rosangela.canuto{at}unito.it

Clofibrate is a hypolipidemic drug belonging to the peroxisome proliferator (PP) family. PPs are well recognized hepatocarcinogens, though only for rodents and not for man. Their oncogenicity is usually ascribed to mitogenic or antiapoptotic action. However, we have reported that clofibrate can trigger fast and extensive apoptosis in rodent and human tumor cell lines. The present paper examines the possible mechanisms involved in clofibrate-induced apoptosis in AH-130 hepatoma cells. The results show that the apoptogenic effect of clofibrate does not depend on induction of PPARs, but on interference with HMGR, a key enzyme which regulates cholesterol biosynthesis and production of isoprenoid units for protein farnesylation. The level and activity of HMGR mRNA are reduced in clofibrate-treated AH-130 cells and apoptosis can be partially prevented by addition of mevalonate. Moreover, cholesterol and cholesterol ester content decreases early in mitochondria and cytocrome c is released in the cytosol. On the contrary, perturbations at the level of protein farnesylation are not important in determining the fast apoptogenic effect, since treatment of AH-130 cells with an inhibitor of farnesyltransferase induces apoptosis only after 4 h. In conclusion, inhibition of HMGR and decreased cholesterol content are crucial events in clofibrate-induced apoptosis in AH-130 hepatoma cells.

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