Role of survivin and alpha 5 integrin in melanoma cell motility and metastasis

Survivin is an Inhibitor of Apoptosis Protein (IAP), which is highly expressed in a number of human malignancies. It is a developmentally regulated gene that is expressed during embryogenesis, but silenced in normal adult tissue. Since its discovery in 1997, survivin function has evolved to include regulation of spindle assembly in mitosis. Melanoma arises in epidermal melanocytes, and is the most lethal dermatologic cancer due to its highly metastatic nature. In melanoma, expression of survivin has been heavily correlated to advanced disease stages and poor patient prognosis. Targeting of survivin in melanoma cells leads to induction of apoptosis in vitro and reduction of tumor growth in vivo. While the anti-apoptotic and mitotic roles of survivin have been extensively studied, the work documented in this dissertation describes a novel basis for survivin function in melanoma metastasis. Chapter 2 details a study which showed that survivin increases melanoma cell migration and invasion via Akt-dependent upregulation of α5 integrin. I also demonstrate that overexpression of survivin increases melanoma colony formation in soft agar, and this effect could be abrogated by knockdown of α5 integrin by RNA interference. These findings demonstrate that survivin can enhance cellular functions which are critical to the metastatic process in melanoma. To further investigate the functional role of survivin and α5 integrin in melanoma metastasis, I used a iv xenograft mouse model to determine the in vivo effect of survivin overexpression and subsequent upregulation of α5 integrin on melanoma metastasis (Chapter 3). The studies show that while survivin overexpression does not result in increased tumor proliferation or decreased apoptosis, it does cause increased metastasis of melanoma cells in vivo and this requires upregulation of α5 integrin. Taken together, this dissertation presents data to support an additional role for survivin function in melanoma metastasis which is α5 integrin-dependent. In summary (Chapter 4), I will discuss future research avenues looking mechanistically at how survivin upregulates α5 integrin and mediates melanoma metastasis. Additionally, I will also discuss therapeutic targeting of survivin and α5 integrin in melanoma and how the knowledge gained in this study may contribute to such efforts.