Journal Article

β‐ TrCP overexpression enhances cisplatin sensitivity by depleting BRCA1

González‐Moreno, Mónica, Belmonte‐Fernández, Alejandro, Jiménez‐Guerrero, Rocío, Sáez, Carmen, Japón, Miguel Á., Romero, Francisco, Pérez‐Valderrama, Begoña, Herrero‐Ruíz, Joaquín, Rodríguez‐Cordero, Laura

2026

Overview

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.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / beta-Transducin Repeat-Containing Proteins - genetics / beta-Transducin Repeat-Containing Proteins - metabolism / BRCA1 / BRCA1 protein / BRCA1 Protein - genetics / BRCA1 Protein - metabolism / cancer / Cancer Therapies / Cancer Therapy Resistance / Carrier Proteins - metabolism / Cell cycle / Cell Line, Tumor / Chemotherapy / Cisplatin / Cisplatin - pharmacology / Cloning / DNA Damage / DNA Damage - drug effects / DNA repair / DNA Repair - drug effects / Drug Resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Enzymes / Eukaryotes / Homologous recombination / Humans / Kinases / Medical prognosis / Nuclear Proteins - metabolism / Prostate / Proteasomes / Proteins / Proteolysis - drug effects / siRNA / Tumor cell lines / Tumorigenesis / Tumors / Ubiquitin-protein ligase / β‐TrCP