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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Viral, Tumor / genetics
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Antigens, Viral, Tumor / metabolism
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Antineoplastic Agents / pharmacology*
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Carcinoma, Merkel Cell / drug therapy*
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Carcinoma, Merkel Cell / genetics
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Carcinoma, Merkel Cell / metabolism
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Carcinoma, Merkel Cell / virology
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Cell Line, Tumor
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Cell Transformation, Viral / drug effects*
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Cell Transformation, Viral / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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HSP70 Heat-Shock Proteins / antagonists & inhibitors*
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HSP70 Heat-Shock Proteins / biosynthesis
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HSP70 Heat-Shock Proteins / genetics
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Humans
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Mice
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Mice, Inbred NOD
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Polyomavirus / genetics
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Polyomavirus / metabolism*
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Polyomavirus Infections / drug therapy*
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Polyomavirus Infections / genetics
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Polyomavirus Infections / metabolism
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Tumor Virus Infections / drug therapy*
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Tumor Virus Infections / genetics
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Tumor Virus Infections / metabolism
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Tumor Virus Infections / pathology
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Xenograft Model Antitumor Assays
Substances
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Antigens, Viral, Tumor
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Antineoplastic Agents
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HSP70 Heat-Shock Proteins
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Neoplasm Proteins
Grants and funding
This study was supported by the Wilhelm-Sander-Stiftung (grant number: 2007.057.3) (
http://www.wilhelm-sander-stiftung.de). This publication was funded by the German Research Foundation (DFG) and the University of Würzburg in the funding programme Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.