Abstract
Clofibrate is a hypolipidemic drug belonging to the peroxisome proliferator (PP) family. PPs are well-recognized hepatocarcinogens, though only for rodents and not for humans. 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 study 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 peroxisome proliferator activated receptors (PPARs), but on interference with HMG-CoA reductase (HMGR), a key enzyme that 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.
Highlights
Clofibrate is a hypolipidemic drug belonging to the peroxisome proliferator (PP) family
The results show that the apoptogenic effect of clofibrate does not depend on induction of peroxisome proliferator activated receptors (PPARs), but on interference with HMG-CoA reductase (HMGR), a key enzyme that regulates cholesterol biosynthesis and production of isoprenoid units for protein farnesylation
Since the failure to stimulate PPAR␣ caused a failure of peroxisome proliferation as well as of oxygen free radical production, whose possible consequence is lipid peroxidation, the effect of clofibrate was examined in terms of lipid peroxidation
Summary
Clofibrate is a hypolipidemic drug belonging to the peroxisome proliferator (PP) family. The induction of peroxisomal enzymes can result in overproduction of reactive oxygen species that may initiate lipid peroxidation and stimulate apoptosis in different cell types [13] In virtue of this induced free radical generation, PPs might exert some genotoxicity on target cells, which has been suggested as an alternative or additional mechanism accounting for their oncogenic action. Shabalina et al [20] reported that another potent PP in rodents, perfluorooctanoic acid, can perturb the proliferative cycle and trigger apoptosis in human HepG2 cells Both human (HepG2) and rat (FAO) hepatoma cells apoptose when exposed to BR931, yet another hypolipidemic drug endowed with PP properties Apart from cells of hepatic lineages, wherein PPAR␣ is thought to play a major role in mediating PP actions, apoptosis has been observed in various other cell types, such as human and mouse breast cancer cells or human lung cancer cells, on exposure to various synthetic or natural ligands of another member of the PP-receptor family, PPAR␥ [21, 22]
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