Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany.
Departments of Chemistry and Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2014 Apr 2;9(4):e92041. doi: 10.1371/journal.pone.0092041. eCollection 2014.
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.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种罕见且高度侵袭性的神经内分泌皮肤癌，目前尚无有效的治疗方法。MCC 是一种具有人类癌症特征的肿瘤，有大量实验证据表明多瘤病毒在其中起致病作用。多瘤病毒编码的大 T 抗原（Large T antigen，LTA）是致癌蛋白，被认为需要细胞热休克蛋白 70（Heat shock protein 70，HSP70）的支持才能发挥其转化活性。在这里，我们评估了 MAL3-101（一种合成的 HSP70 抑制剂）抑制各种 MCC 细胞系增殖和存活的能力。值得注意的是，MAL3-101 治疗可导致 7 种 MCC 细胞系中的 5 种产生明显的细胞凋亡。虽然这种作用与 MCC 细胞的病毒状态无关，但对已知 HSP70 同工型的定量 mRNA 表达分析显示，MAL3-101 敏感性与 HSC70 表达之间存在显著相关性，HSC70 是所有细胞系中最突出的同工型。此外，MAL3-101 还在 MCC 异种移植模型中显示出体内抗肿瘤活性，表明这种物质或相关化合物可能是未来治疗 MCC 的潜在治疗药物。
