Abstract
Melanoma is the most serious, highly aggressive form of skin cancer with recent dramatic increases in incidence. Current therapies are relatively ineffective, highlighting the need for a better understanding of the molecular mechanisms contributing to the disease. We have previously shown that activation of Rap1 promotes melanoma cell proliferation and migration through the mitogen-activated protein kinase pathway and integrin activation. In the present study, we show that expression of Rap1GAP, a specific negative regulator of Rap1, is decreased in human melanoma tumors and cell lines. Overexpression of Rap1GAP in melanoma cells blocks Rap1 activation and extracellular signal-regulated kinase (ERK) phosphorylation and inhibits melanoma cell proliferation and survival. In addition, overexpression of Rap1GAP also inhibits focal adhesion formation and decreases melanoma cell migration. Rap1GAP down-regulation is due to its promoter methylation, a mechanism of gene silencing in tumors. Furthermore, treatment of melanoma cells with the demethylating agent 5-aza-2'-deoxycytidine reinduces Rap1GAP expression, followed by decreased Rap1 activity, ERK phosphorylation, and cell proliferation and survival-changes that are significantly blunted in cells transfected by small interfering RNA-mediated Rap1GAP knockdown. Taken together, our findings indicate that down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.
Highlights
Melanoma is the most serious, highly aggressive form of skin cancer whose incidence has increased at a rate greater than that of any other cancer type in the United States.5 Recently, targeted melanoma therapies have been developed based upon molecular insights into tumor pathogenesis but have shown relative ineffectiveness to date when used as a monotherapy [1]
To characterize the role of Rap1GAP in melanoma tumorigenesis, we first examined its expression in human melanoma tumors and cell lines
Decreased or absent Rap1GAP expression was found in cutaneous (15138 and 33221) and metastatic (14583, 16151, 11771, 13488, and 14150) melanoma tumors compared with human epidermal melanocytes (HEM; Fig. 1A)
Summary
Melanoma is the most serious, highly aggressive form of skin cancer whose incidence has increased at a rate greater than that of any other cancer type in the United States. Recently, targeted melanoma therapies have been developed based upon molecular insights into tumor pathogenesis (such as receptor kinase inhibitors) but have shown relative ineffectiveness to date when used as a monotherapy [1]. Melanoma is the most serious, highly aggressive form of skin cancer whose incidence has increased at a rate greater than that of any other cancer type in the United States.. Targeted melanoma therapies have been developed based upon molecular insights into tumor pathogenesis (such as receptor kinase inhibitors) but have shown relative ineffectiveness to date when used as a monotherapy [1]. The lack of therapeutic response to currently available treatment highlights the importance of improved understanding of the complex molecular mechanism(s) that contribute to melanoma development. The RAS/BRAF/extracellular signal-regulated kinase (ERK) pathway plays a central role in the development of most types of. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Phone: 314-362-8187; Fax: 314-362-8159; E-mail: cornelil@ msnotes.wustl.edu
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