Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth

Abstract

We have previously demonstrated that the thiazolidinedione ciglitazone inhibited, independently of PPARc activation, melanoma cell growth. Further investigations now show that ciglitazone effects are mediated through the regulation of secreted factors. Q-PCR screening of several genes involved in melanoma biology reveals that ciglitazone inhibits expression of the CXCL1 chemokine gene. CXCL1 is overexpressed in melanoma and contributes to tumorigenicity. We show that ciglitazone induces a diminution of CXCL1 level in different human melanoma cell lines. This effect is mediated by the downregulation of microphthalmia-associated transcription factor, MITF, the master gene in melanocyte differentiation and involved in melanoma development. Further, recombinant CXCL1 protein is sufficient to abrogate thiazolidinedione effects such as apoptosis induction, whereas extinction of the CXCL1 pathway mimics phenotypic changes observed in response to ciglitazone. Finally, inhibition of human melanoma tumor development in nude mice treated with ciglitazone is associated with a strong decrease in MITF and CXCL1 levels. Our results show that anti-melanoma effects of thiazolidinediones involve an inhibition of the MITF/ CXCL1 axis and highlight the key role of this specific pathway in melanoma malignancy. Cell Death and Differentiation (2011) 18, 109-121; doi:10.1038/cdd.2010.75; published online 2 July 2010Cutaneous melanoma is an aggressive skin cancer that originates from epidermal melanocytes. Melanoma development is accomplished through the accumulation of genetic alterations in growth control pathways including oncogenic mutations or gene amplification. For example, constitutive activation of the Ras/MAPkinase-signaling pathway is frequently observed in melanomas, as a consequence of activating mutations of the B-Raf and N-Ras genes. 1-3Melanoma progression is also accompanied by generation of autocrine and paracrine loops associated with the aberrant production and secretion of growth factors and chemokines that sustain growth, survival and invasion. 4 In humans, melanoma is one of the most lethal cancers among young adults. Melanoma has a high capability of invasion and rapid metastasis to other organs. The prognosis of metastatic melanoma is extremely dismal, as the various treatments have not shown survival benefit.5 It appears thus necessary to develop approaches enabling the discovery of new molecular targets, candidates for specific biotherapy treatment of this disease.Thiazolidinediones (TZDs) regulate transcriptional activity of the nuclear receptor peroxysome proliferator activated receptor g (PPARg) and are currently used in type II diabetes treatment. More recently, TZD have been reported to inhibit proliferation and survival of numerous cancer cells. 6 Furthermore, we have previously demonstrated that ciglitazone, which belongs to TZD family, inhibits growth and viability of melanoma cells without affecting normal melanocyte growth. 7To further investigate the molecular events elicited by ciglitazone and to b...

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