IGF1R Induces ROS Formation in Mitochondria via MICU1 Leads to the Enzalutamide Resistance in Prostate Cancer

ABSTRACT

After undergoing ADT treatment, drug resistance has emerged as a major hindrance in the treatment of prostate cancer, with enzalutamide resistance being the most notable. Our objective was to identify a new drug‐resistance mechanism present in post‐ADT‐treatment patients. Utilizing proteomic sequencing, we discovered abnormal increases in IGF1R levels. Subsequent sequencing and bioinformatic analyses showed that IGF1R could cause abnormal changes in the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation. This phenomenon may be due to IGF1R's influence on the distribution of mitochondrial Ca ²⁺ and the production of reactive oxygen species (ROS). Our CHIP and dual‐luciferase experiments confirmed the regulatory relationship between IGF1R and MICU1. The fluorescent results of Ca ²⁺ and ROS also confirmed that IGF1R could regulate mitochondrial Ca ²⁺ distribution and ROS production. Our team validated the relationship between IGF1R and drug resistance through cell phenotype experiments, and explored its potential as a therapeutic target through a fa‐ci curve. Finally, we verified the effectiveness of the mechanisms we found through a xenograft assay. Our study confirms the potential for IGF1R as a clinical therapeutic target.