β-TrCP overexpression enhances cisplatin sensitivity by depleting BRCA1.

Abstract

Cisplatin is one of the most used anticancer chemotherapy agents; however, over time, patients develop resistance to the treatment, and survival rates drop dramatically. Investigation of tumor cell resistance mechanisms could increase sensitivity and prevent cancer progression. Here, we investigated the role of the E3 ubiquitin ligase SCF (β-TrCP) in cisplatin resistance in different tumor cell lines, analyzing its role in the stability of BRCA1 and CtIP, proteins involved in DNA damage repair by homologous recombination. We showed that SCF(β-TrCP) plays a key role in cisplatin response, as overexpression of wild-type β-TrCP increased DNA damage and cisplatin-induced apoptosis, while overexpression of a dominant-negative mutant or siRNA-mediated downregulation of β-TrCP decreased the damage and conferred treatment resistance. Furthermore, we demonstrated that BRCA1 and CtIP interacted with β-TrCP in vivo, and their levels changed when β-TrCP expression was modulated. We also described that β-TrCP-mediated BRCA1 degradation involves both lysosomal and proteasomal pathways. Mechanistically, the failure of β-TrCP to regulate the degradation of BRCA1 enables a more efficient DNA damage repair and thereby the acquisition of cisplatin resistance. Overall, β-TrCP overexpression sensitizes cisplatin-induced DNA damage by depleting BRCA1.