Peroxisome proliferator-activated receptor alpha activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt.
OBJECTIVE
Peroxisome proliferator-activated receptors (PPAR) regulate lipid and glucose metabolism but their anticancer properties have been recently studied as well. We previously reported the antimetastatic activity of the PPARalpha ligand, fenofibrate, against melanoma tumors in vivo. Here we investigated possible molecular mechanisms of fenofibrate anti metastatic action.


METHODS
Monolayer cultures of mouse (B16F10) and human (SkMell88) melanoma cell lines, soft agar assay, and cell migration assay were used in this study. In addition, we analyzed PPARalpha expression and its transcriptional activity in response to fenotibrate by using Western blots and liciferase-based reporter system.


RESULTS
Fenofibrate inhibited migration of B16F10 and SkMel188 cells in Transwell chambers and colony formation in soft agar. These effects were reversed by PPAR inhibitor, GW9662. Western blot analysis revealed time-dependent down-regulation of Akt and extracellular signal-regulated kinase l/2 phosphorylation in fenofibrate-treated cells. A B16F10 cell line stably expressing constitutively active Akt mutant was resistant to fenofibrate. In contrast, Akt gene silencing with siRNA mimicked the fenofibrate action and reduced the migratory ability of B16F1O cells. In addition, fenofibrate strongly sensitized BI6FIO cells to the proapoptotic drug staurosporine, further supporting the possibility that fenofibrate-induced down-regulation of Akt function contributes to fenofibrate-mediated inhibition of metastatic potential in this experimental model.


CONCLUSIONS
Our results show that the PPAR-dependent antimetastatic activity of fenofibrate involves down-regulation of Akt phosphorylation and suggest that supplementation with this drug may improve the effectiveness of melanoma chemotherapy.
Grabacka
Maja
M
Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania 19122, USA.
Plonka
Przemyslaw M
PM
Urbanska
Krystyna
K
Reiss
Krzysztof
K
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000503:physiopathology; D047493:PPAR alpha / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019311:Staurosporine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine; D011345:Fenofibrate