title: Caspase 2 activation and ER stress drive rapid Jurkat cell apoptosis by clofibrate.
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 Ca(2+) 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.
authors.affiliation: Department of Experimental Medicine and Oncology, University of Torino, Torino, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Penna
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pin
authors.forename: Domiziana
authors.initials: D
authors.lastname: Costamagna
authors.forename: Patrizia
authors.initials: P
authors.lastname: Reffo
authors.forename: Francesco Maria
authors.initials: FM
authors.lastname: Baccino
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bonelli
authors.forename: Paola
authors.initials: P
authors.lastname: Costelli
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002994:Clofibrate / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D053143:Caspase 2; D002994:Clofibrate