Dynamic regulation and physical interaction of IGF1 and CYR61 in prostate cancer cells

Prostate cancer (PCa) remains a leading cause of cancer-related mortality among men, with limited treatment options for advanced disease. Cysteine-rich angiogenic inducer 61 (CYR61), a matricellular protein with an insulin-like growth factor-binding domain, has been implicated in tumorigenesis, yet its role in PCa progression is incompletely understood. Given our published studies validating that silencing CYR61 impaired proliferation, migration, and PI3K/AKT signaling, while PI3K/AKT inhibition abrogated insulin-like growth factor-1 (IGF1)-induced CYR61 expression and proliferation, and the established involvement of IGF1 in PCa and its association with therapy resistance, this study specifically investigated the molecular interplay between IGF1 and CYR61. Our studies by confocal microscopy revealed that IGF1 induces nuclear CYR61 expression and translocation in a time-dependent manner across PC3, 22Rv1, and LNCaP cells, with maximal expression observed at 24 hours post-treatment. Immunoprecipitation assays also demonstrated a physical interaction between IGF1 and CYR61 in PC3 and HEK293T cells, suggesting direct or complex-mediated binding. These findings position CYR61 as a critical effector of IGF1 signaling and raise the possibility of extracellular interactions that modulate PCa progression. Ongoing studies using the AVEXIS system aim to define the IGF1-CYR61 interactome and identify additional binding partners, which may uncover novel therapeutic targets and biomarkers. Future directions include mapping these interactions in tumor microenvironment compartments and exploring combinatorial strategies integrating CYR61 inhibition with IGF1R or PI3K inhibitors to curb aggressive PCa.