Abstract
Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.
Highlights
Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer, which primarily affects elderly or immunocompromised individuals [1,2]
MCC cells depend on large T antigen (LTA) and its ability to interact with Retinoblastoma protein (Rb) [12]
To confirm that HSC70 mRNA levels correlated with protein expression, we performed immunohistochemistry with cells of the respective MCC cell lines embedded in a bovine plasma/thrombin clot prior to formalin fixation
Summary
Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer, which primarily affects elderly or immunocompromised individuals [1,2]. MCC is a rare disease, but its incidence is rapidly increasing [3,4]. Therapeutic options for advanced disease are of limited efficacy with no proven benefit on overall survival [7,8,9,10,11]. MCC is associated in the majority of cases with Merkel cell polyoma virus (MCPyV). MCC represents the human cancer with the best experimental evidence for a causal role of a polyoma virus, and expression of the T antigens by MCPyV is required for growth of MCC cells in cell culture and in xenografts [12,13]. MCC cells depend on large T antigen (LTA) and its ability to interact with Retinoblastoma protein (Rb) [12]. It is believed that this interaction requires the activity of a cellular heat shock protein 70, or HSP70 [14]
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