Identification of New Molecular Targets for Treatment of Endometrial Cancers

Abstract

Background: Current approaches using molecularly targeted drug alone or in combination with cytotoxic agents are associated with varying degrees of response rates and adverse effects. Clearly, there is a need to identify new molecular targets with more selectivity against the endometrial cancer cells. Aim: To perform high throughput screening to identify and validate new molecular targets for treatment of endometrial cancers. Methods: Kinome-wide shRNA library screen was performed on endometrial cancer cell line. The results were validated using viability and apoptosis assay. Immunoblotting assay was conducted to identify the target protein. Results: We identified that the knock-down of endogenous cyclin-dependent kinases regulatory subunit 1B (CKS1B) induced significant cell death in a panel of endometrial cancer cell lines (AN3CA, HEC-1A, HEC-1B, RL-95 and Ishikawa). In contrast, no significant cytotoxicity was observed in the THESC nontransformed endometrial epithelial cells suggesting that CKS1B is mediating a tumor-specific survival pathway. Analysis by immunoblotting assay revealed an increased of p27 protein expression following depletion of endogenous CKS1B in the type 2 endometrial cancer cells (AN3CA and HEC-1A), while no changes was observed in the type 1 (Ishikawa and RL95-2) endometrial cancer cells. These results suggest that CKS1B might regulate the survival of type I and type II endometrial cancer cells through distinct mechanisms. Conclusion: The results demonstrated that inhibition of CKS1B induced significant tumor-specific cell death in endometrial cancer cells. We found that the response is significant in type 2 endometrial cancer cell line and is p27 dependent. This finding suggests that CKS1B could be a potential target for therapeutic intervention and warrant further investigation.