PPARalpha and PP2A are involved in the proapoptotic effect of conjugated linoleic acid on human hepatoma cell line SK-HEP-1.
Conjugated linoleic acid (CLA), found in dairy products, in beef and lamb has been demonstrated to possess anticancer properties protecting several tissues from developing cancer. Moreover, it has been shown to modulate apoptosis in several cancer cell lines. The aim of this study was to investigate which signaling transduction pathways were modulated in CLA-induced apoptosis in human hepatoma SK-HEP-1 cells. The cells exposed to CLA were evaluated for PPARalpha, PP2A, pro-apoptotic proteins Bak, Bad and caspases, and anti-apoptotic proteins Bcl-2 and Bcl-X(L). Cells were also treated with okadaic acid, a PP2A inhibitor, or with Wy-14643, a specific PPARalpha agonist. The CLA-induced apoptosis was concomitant to the increase of percentage of cells in the S phase, PPARalpha, PP2A and pro-apoptotic proteins; simultaneously, antiapoptotic proteins decreased. Inhibition of PP2A prevented apoptosis, and PPARalpha agonist showed similar effect as CLA. The increased PP2A could be responsible for the dephosphorylation of Bcl-2 and Bad, permitting apoptotic activity of Bax and Bad. The increase of caspase 8 and 9 suggested that both the intrinsic and extrinsic apoptotic pathways were induced. PP2A was probably increased by PPARalpha, since putative PPRE sequences were found in genes encoding its subunits. In conclusion, CLA induces apoptosis in human hepatoma SK-HEP-1 cells, by increasing PPARalpha, PP2A and pro-apoptotic proteins.
Muzio
Giuliana
G
Dipartimento di Medicina ed Oncologia Sperimentale, Università di Torino, Corso Raffaello Torino, Italy.
Maggiora
Marina
M
Oraldi
Manuela
M
Trombetta
Antonella
A
Canuto
Rosa Angela
RA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism*; D008969:Molecular Sequence Data; D019319:Okadaic Acid / Q000494:pharmacology; D047493:PPAR alpha / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C494819:BAD protein, human; C494772:BAK1 protein, human; D004273:DNA, Neoplasm; D047493:PPAR alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019319:Okadaic Acid; C006253:pirinixic acid; D019787:Linoleic Acid; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; D020169:Caspases