Abstract
Differently from the antiapoptotic action most commonly assigned to peroxisome proliferators (PPs), we demonstrated that some of them, clofibrate (CF) in particular, display clearcut apoptogenic properties on rat hepatoma cell lines. We and others could confirm that CF as well as various other PPs can induce apoptosis in a variety of cells, including human liver, breast and lung cancer cell lines. The present study was aimed at investigating the cytotoxic action of CF on a neoplastic line of different origin, the human T leukemia Jurkat cells. We observed that CF rapidly triggers an extensive and morphologically typical apoptotic process on Jurkat cells, though not in primary T cells, which is completely prevented by the polycaspase inhibitor zVADfmk. Gene silencing studies demonstrated that CF-induced apoptosis in Jurkat cells is partially dependent on activation of caspase 2. Looking for a possible trigger of caspase 2 activation, we observed increased levels of phosphorylated eIF2α and JNK in CF-treated cells. Moreover, intracellular Ca2+ homeostasis was perturbed. Together, these findings are suggestive for the occurrence of ER stress, an event that is known to have the potential to activate caspase 2. The present observations demonstrate that CF induces in Jurkat cells a very fast and extensive apoptosis, that involves induction of ER stress and activation of caspases 2 and 3. Since apoptosis in Jurkat cells occurs at pharmacologically relevant concentrations of CF, the present findings encourage further in depth analysis in order to work out the potential implications of CF cytotoxcity on leukemic cells.
Highlights
Clofibrate (CF) and other fibrate derivatives have long been used as hypolipidemic drugs [1]
When exposed to 1 mM CF for 45 min, the standard treatment schedule adopted throughout the present work, approximately 50% of Jurkat cells develop a frankly apoptotic morphology characterized by cell shrinkage due to nuclear and cytoplasmic condensation with nuclear fragmentation (Fig. 1A–B)
Triggers a caspase-dependent apoptotic process not conforming to a canonical pathway, wherein caspases 2, likely activated by ER stress, and caspase 3 are involved. Both apoptosis and caspase 3 activation are prevented by Ca2+ influx, suggesting that mobilization of Ca2+ stores from the ER combined with suppression of Ca2+ influx are as well a crucial event in the pathway to cell death
Summary
Clofibrate (CF) and other fibrate derivatives have long been used as hypolipidemic drugs [1] These compounds are part of a largely heterogeneous class of chemicals known as peroxisome proliferators (PPs). Their mechanism of action typically requires binding to heterodimeric nuclear receptors in which a monomer of RXR combines with a monomer of PP-activated receptor (PPAR). When administered to rats and mice they induce peroxisome proliferation, hepatomegaly, and hepatocarcinogenesis [4,5]. By contrast, these effects cannot be observed in monkeys, pigs and humans [6,7,8]. Despite observations that various PPARa ligands exert a prosurvival action that was suggested to contribute to their carcinogenic potential [12], some of them have been demonstrated to induce apoptosis in different hepatoma cell lines
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