There is increasing recognition that apoptotic cell death is a key factor restraining tumor development, and that dysfunctional apoptosis is a common feature of cancer cells leading to therapeutic failure. This is particularly true for melanoma, which is usually resistant to radiation and chemotherapeutic drugs that eliminate cells through induction of apoptosis. Thus, understanding the molecular basis for this apoptosis resistance has tremendous clinical relevance. The long-term goals of this project are to understand how apoptosis is regulated in melanocytic cells, and how dysregulation of this process may lead to mel'anoma and confer resistance to therapy. Previously, we found that an inhibitor of apoptosis termed Survivin is expressed in melanoma but not in normal melanocytes, and that blocking Survivin triggers spontaneous apoptosis in melanoma cells. Our hypothesis, based on these and additional preliminary observations, is that Survivin expression contributes to the progression from normal melanocyte to melanoma and may represent an important viability factor for melanoma cells.
Three specific aims are proposed. 1) To study the consequences of Survivin expression in melanocytes. We will use both adenoviral and transgenic-based approaches to define the role of Survivin expression in melanocyte transformation. 2) To examine biochemical events resulting from Survivin inhibition in melanoma. We will use cell lines expressing inducible Survivin mutants to investigate caspase-dependent and mitochondrial events leading to apoptosis upon Survivin targeting. 3) To investigate the regulation of caspase-independent apoptotic events associated with Survivin inhibition. These experiments will focus on the roles of mitochondrial apoptosis-inducing factor and cleavage of a Survivin-like molecule (Livin) in melanocytes and melanoma cells. In summary, these proposed studies promise to elucidate mechanisms of apoptosis regulation in normal and malignant melanocytes, and may identify new molecular approaches for therapeutic intervention in cancer. ? ?
| McKenzie, Jodi A; Liu, Tong; Jung, Jae Y et al. (2013) Survivin promotion of melanoma metastasis requires upregulation of ?5 integrin. Carcinogenesis 34:2137-44 |
| Jenkins, N C; Liu, T; Cassidy, P et al. (2011) The p16(INK4A) tumor suppressor regulates cellular oxidative stress. Oncogene 30:265-74 |
| McKenzie, Jodi A; Liu, Tong; Goodson, Agnessa G et al. (2010) Survivin enhances motility of melanoma cells by supporting Akt activation and {alpha}5 integrin upregulation. Cancer Res 70:7927-37 |
| Goodson, Agnessa Gadeliya; Florell, Scott R; Boucher, Kenneth M et al. (2010) Low rates of clinical recurrence after biopsy of benign to moderately dysplastic melanocytic nevi. J Am Acad Dermatol 62:591-6 |
| Goodson, Agnessa Gadeliya; Grossman, Douglas (2009) Strategies for early melanoma detection: Approaches to the patient with nevi. J Am Acad Dermatol 60:719-35; quiz 736-8 |
| LaBarbera, Daniel V; Modzelewska, Katarzyna; Glazar, Amanda I et al. (2009) The marine alkaloid naamidine A promotes caspase-dependent apoptosis in tumor cells. Anticancer Drugs 20:425-36 |
| Raj, Deepak; Liu, Tong; Samadashwily, George et al. (2008) Survivin repression by p53, Rb and E2F2 in normal human melanocytes. Carcinogenesis 29:194-201 |
| Florell, Scott R; Smoller, Bruce R; Boucher, Kenneth M et al. (2008) Sampling of melanocytic nevi for research purposes: a prospective, pilot study to determine effect on diagnosis. J Am Acad Dermatol 59:814-21 |
| Florell, Scott R; Meyer, Laurence J; Boucher, Kenneth M et al. (2008) Increased melanocytic nevi and nevus density in a G-34T CDKN2A/p16 melanoma-prone pedigree. J Invest Dermatol 128:2122-5 |
| Thomas, Joshua; Liu, Tong; Cotter, Murray A et al. (2007) Melanocyte expression of survivin promotes development and metastasis of UV-induced melanoma in HGF-transgenic mice. Cancer Res 67:5172-8 |
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