Mechanisms involved in growth inhibition induced by clofibrate in hepatoma cells.
Low concentrations of some peroxisome proliferators have been found to decrease apoptosis in rat liver cells, whereas higher but pharmacological concentrations have been found to inhibit cell proliferation or to induce apoptosis in human and rat hepatoma cells. The highly deviated JM2 rat hepatoma cell line was used to examine the mechanisms underlying the inhibitory effect on cell proliferation. Clofibrate chiefly inhibited cell proliferation in these cells. Parallel to the decrease in cell proliferation there was an increase of peroxisome proliferator activated receptor (PPAR) gamma and of protein phosphatase 2A, whose importance was confirmed, respectively, by using antisense oliginucleotides (AS-ODN) or okadaic acid. The increase of protein phosphatase 2A induced by PPARgamma caused a decrease of MAPK, an intracellular signaling transduction pathway, as shown by evaluation of Erk1,2 and c-myc. In light of these results, clofibrate, like conventional synthetic ligands of PPARgamma, may be regarded as a possible prototype anti-tumour drug.
Muzio
Giuliana
G
Dipartimento di Medicina ed Oncologia Sperimentale, Università di Torino, Corso Raffaello 30, Italy.
Maggiora
Marina
M
Trombetta
Antonella
A
Martinasso
Germana
G
Reffo
Patrizia
P
Colombatto
Sebastiano
S
Canuto
Rosa Angela
RA
D000818:Animals; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D002994:Clofibrate / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D019319:Okadaic Acid / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000187:drug effects; D054648:Protein Phosphatase 2; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019319:Okadaic Acid; D007770:L-Lactate Dehydrogenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D002994:Clofibrate