Selinexor targets expression of metabolic genes in Merkel cell carcinoma cells

Abstract

Background: Merkel cell carcinoma (MCC) is a deadly skin cancer that primarily affects the elderly and immunocompromised, with mortality rates ranging from 50% to 80%. Merkel cell polyomavirus (MCPyV) is associated with 80% of cases of MCC. The primary treatment for MCC is immune checkpoint inhibitors; however, many patients are unresponsive to or do not meet criteria for treatment. The Warburg effect has linked cancer cell survival to increased glycolytic metabolism to maintain increased cellular energy demands. While initial hypotheses suggested that increased glycolysis itself was directly upregulated and important in cancer cell proliferation, more recent ideas suggest a "moonlighting" role for glycolysis genes. In general, these "moonlighting" proteins' non-metabolic functions are equally as important if not more important than their catalytic functions.Previous research on MCPyV-positive MCC demonstrated that selinexor targeted and decreased the expression of viral T antigens, inhibited the DNA damage response, and downregulated lipogenesis proteins. More recently, these metabolic genes have been found to regulate many oncogenes and tumor suppressors. Selinexor, an approved treatment for multiple myeloma, acts as a selective inhibitor of nuclear export by blocking exportin 1 and blocking translation of key proto-oncogenes.Objectives: Here, we report the effects of selinexor on expression of glycolytic and metabolic genes, speci cally discussing the catalytic effects on metabolic function and their indirect non-catalytic effects.Methods: Immunoblotting quanti ed through densitometric analysis determined the protein expression in MS-1 cell lines. T-tests were used to determine statistical signi cance.Results: Analysis revealed highly statistically signi cant (p<0.001) or statistically signi cant (p<0.01) downregulations of protein expression of GLUD1, GLUT3, Hexokinase 1, PFKFB2, amphiregulin, LDHA, PDHK1, and MCT1. Conclusion:In the MCC cell line MS-1, selinexor signi cantly downregulated expression of many genes in cellular energy metabolism and cellular proliferation in a statistically signi cant relevant manner. These results suggest that selinexor may be a novel viable option for the treatment of MCC, but further studies in vivo and clinical trials are required to validate these ndings.