期刊
CANCER LETTERS
卷 524, 期 -, 页码 259-267出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.10.031
关键词
Targeted therapy; Polyomavirus; GSK3 knockdown; GSK3 knockout
类别
资金
- German Cancer Aid [70112438]
- German Research Foundation [HO5280/2-2]
GSK3 inhibitors, such as CHIR99021, have been identified as potential therapeutics for Merkel cell carcinoma (MCC) by repressing TA expression in MCC cells, demonstrating in vivo antitumor activity in a MCC xenograft mouse model. This study provides a promising approach for future treatment of MCC by targeting virus-encoded T antigens.
Merkel cell carcinoma is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). Since proliferation of MCPyV-positive MCC tumor cells strictly depends on expression of the virus-encoded T antigens (TA), these proteins theoretically represent ideal targets for different kinds of therapeutic approaches. Here we developed a cell-based assay to identify compounds which specifically inhibit growth of MCC cells by repressing TA expression. Applying this technique we screened a kinase inhibitor library and identified six compounds targeting glycogen synthase kinase 3 (GSK3) such as CHIR99021 as suppressors of TA transcription in MCC cells. Involvement of GSK3 alpha and -beta in the regulation of TA-expression was confirmed by combining GSK3A knockout with inducible GSK3B shRNA knockdown since double knockouts could not be generated. Finally, we demonstrate that CHIR99021 exhibits in vivo antitumor activity in an MCC xenograft mouse model suggesting GSK3 inhibitors as potential therapeutics for the treatment of MCC in the future.
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