PPAR γ regulates MITF and β‐catenin expression and promotes a differentiated phenotype in mouse melanoma S91

Abstract

Melanoma represents one of the most rapidly metastasizing, hence deadly tumors due to its high proliferation rate and invasiveness, characteristics of undifferentiated embryonic tissues. Given the absence of effective therapy for metastatic melanoma, understanding more fully the molecular mechanisms underlying melanocyte differentiation may provide opportunities for novel therapeutic intervention. Here we show that in mouse melanoma S91 cells activation of the peroxisome proliferator activated receptor (PPAR) gamma induces events resembling differentiation, such as growth arrest accompanied by apoptosis, spindle morphology and enhanced tyrosinase expression. These events are preceded by an initial transient increase in expression from the Microphthalmia-associated transcription factor gene, (MITF) promoter, whereas exposure to a PPAR gamma ligand- ciglitazone that exceeds 8 h, causes a gradual decrease of MITF, until by 48 h MITF expression is substantially reduced. Beta-catenin, an MITF transcriptional activator, shows a similar pattern of decline during ciglitazone treatment, consistent with previous reports that activated PPAR gamma inhibits the Wnt/beta-catenin pathway through induction of beta-catenin proteasomal degradation. We suggest that the PPAR gamma-mediated beta-catenin down-regulation is likely to be responsible for changes in MITF levels. The data suggest that PPAR gamma, besides its well-established role in mesenchymal cell differentiation towards adipocytes, might regulate differentiation in the melanocytic lineage.

Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth

“…One possible mechanism might involve downregulation of the Wnt/b-catenin pathway because this pathway is inhibited by some PPARg agonists and might mediate the inhibition of MITF expression. 17,18 Thus, considering all our results we show for the first time that the control of MITF expression by ciglitazone is involved in the inhibition of CXCL1 expression and secretion. This new signaling pathway involves MITF in the regulation of CXCL1 and strengthens the importance of this transcription factor in melanoma tumorigenicity.…”

“…To further investigate the mechanism responsible for ciglitazone-induced CXCL1 downregulation, we focused our attention on MITF that was recently reported to be regulated by some PPARg agonists. 17,18 Ciglitazone induced a dose-dependent reduction of MITF expression in both A375 and SK-Mel-28 melanoma cells (Figure 7a). We demonstrated that MITF inhibition by ciglitazone was not due to its cleavage during Cytokines Chemokine (C-X-C motif) ligand 1 (melanoma growth-stimulating activity, a) Negative regulation of MITF/CXCL1 axis by TZD T Botton et al apoptosis because the MITF decrease was observed earlier than PARP cleavage.…”

“…It has been proposed that some PPARg agonists lead to inhibition of NF-kB activation, [30][31][32] but in our system, the inhibition of CXCL1 by ciglitazone is not mediated by the downregulation of NF-kB activity (data not shown). Interestingly, a recent paper showed that ciglitazone led to a decrease in MITF expression 17 and in silico analysis of the CXCL1 promoter showed four potential E boxes that match with the consensus binding site for MITF transcription factor (data not shown), thereby suggesting the possible involvement of MITF in the control of CXCL1 expression. These two observations Negative regulation of MITF/CXCL1 axis by TZD T Botton et al prompted us to investigate the role of MITF in the regulation of CXCL1 by ciglitazone.…”

Fenofibrate Increases Radiosensitivity in Head and Neck Squamous Cell Carcinoma via Inducing G2/M Arrest and Apoptosis

“…It has been reported that fenofibrate plays important role in anticancer properties via diverse mechanisms in recent years (Balfour et al, 1990;Pawlik et al, 2004;Saidi et al, 2006;Grabacka et al, 2006;Urbanska et al, 2008;Zak et al, 2010;Wilk et al, 2012;Cho et al, 2013;Zhao et al, 2013;Liang et al, 2013;Watanabe et al, 2013;Li et al, 2014). But the exact relationship between fenofibrate and irradiation has not explored.…”

“…Interestingly, more recent studies suggest that fenofibrate may have an important role as antitumor agents in various cancers such as glioblastoma (Wilk et al, 2012), prostate cancer (Zhao et al, 2013), lung cancer (Liang et al, 2013), breast cancer (Li et al, 2014), endometrial cancer (Saidi et al, 2006), colon cancer (Watanabe et al, 2013), melanoma (Grabacka Jia Liu et al et al, 2006), medulloblastoma (Urbanska et al, 2008) and leukemia (Zak et al, 2010). Fenofibrate decreases metastatic potential of melanoma cells in vitro via downregulation of Akt (Grabacka et al, 2006). Fenofibrate induced apoptosis and decreased proliferation rate in endometrial cancer cells (Saidi et al, 2006), in human and mouse medulloblastoma cell lines (Urbanska et al, 2008), in mantle cell lymphoma (Zak et al, 2010), and in triple-negative breast cancer cells (Li et al, 2014).…”