β-TrCP overexpression enhances cisplatin sensitivity by depleting BRCA1

Area of Science:

• Molecular Oncology
• Cancer Chemotherapy
• Ubiquitin Ligase Function

Background:

• Cisplatin is a widely used chemotherapy agent, but acquired tumor cell resistance significantly limits its efficacy.
• Understanding resistance mechanisms is crucial for improving patient outcomes and overcoming treatment failure.
• The E3 ubiquitin ligase SCF (β-TrCP) regulates protein stability and has been implicated in various cellular processes.

Purpose of the Study:

• To investigate the role of SCF (β-TrCP) in mediating cisplatin resistance in cancer cells.
• To analyze the impact of SCF (β-TrCP) on the stability of BRCA1 and CtIP, key players in DNA repair.
• To elucidate the mechanism by which SCF (β-TrCP) influences cisplatin sensitivity and DNA damage response.

Main Methods:

• Utilized various tumor cell lines to study cisplatin resistance.
• Manipulated β-TrCP expression using overexpression of wild-type and dominant-negative mutants, and siRNA-mediated knockdown.
• Assessed DNA damage, apoptosis, protein-protein interactions (BRCA1, CtIP, β-TrCP), and protein degradation pathways (lysosomal and proteasomal).

Main Results:

• Overexpression of wild-type β-TrCP enhanced DNA damage and cisplatin-induced apoptosis.
• Inhibition of β-TrCP (dominant-negative mutant or siRNA) reduced DNA damage and conferred resistance to cisplatin.
• β-TrCP directly interacted with BRCA1 and CtIP, and its modulation altered their protein levels; β-TrCP-mediated BRCA1 degradation occurs via lysosomal and proteasomal pathways.

Conclusions:

• SCF (β-TrCP) plays a critical role in regulating cisplatin sensitivity by controlling the stability of DNA repair proteins BRCA1 and CtIP.
• Efficient β-TrCP-mediated degradation of BRCA1 is essential for effective DNA damage repair, and its failure leads to cisplatin resistance.
• Targeting β-TrCP or its interaction with BRCA1 may represent a novel strategy to overcome cisplatin resistance in cancer therapy.