IGFBP3–SphK1/S1P Signaling Axis Drives Enzalutamide Resistance in Advanced Prostate Cancer
Year: 2025
Type: article
Abstract: Enzalutamide resistance remains a significant challenge in the treatment of advanced prostate cancer. Identifying molecular drivers of enzalutamide resistance is crucial for developing effective therapeutic strategies. In this study, we identify insulin-like growth factor-binding protein 3 (IGFBP3) as a key driver of enzalutamide resistance in castration-resistant prostate cancer (CRPC). We demonstrate that IGFBP3 expression is significantly upregulated in enzalutamide-resistant C4-2B MDVR cells compared with parental C4-2B cells. This upregulation was consistently observed across multiple enzalutamide-resistant CRPC models, including LNCaP-derived 42D and 42F cells, as well as long-term enzalutamide-resistant cell lines derived from LNCaP, VCaP, LAPC-4, and CWR-R1 cells. Additionally, enzalutamide treatment directly induced IGFBP3 expression in sensitive cells. Elevated IGFBP3 expression was also observed in CRPC patient samples after enzalutamide treatment and was associated with higher Gleason scores and reduced disease-free survival. Mechanistically, IGFBP3 activates the sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway, which promotes cell survival and resistance to enzalutamide. IGFBP3 knockdown decreased SphK1 expression, reduced S1P secretion, and enhanced enzalutamide sensitivity, whereas IGFBP3 overexpression induced SphK1 expression and S1P production, conferring enzalutamide resistance. Inhibition of IGFBP3 via siRNA reduced cell viability, induced apoptosis, and resensitized resistant models to enzalutamide. Similarly, targeting SphK1 with the inhibitor SKI-II suppressed SphK1 activity, reduced S1P production, enhanced enzalutamide sensitivity, and significantly inhibited resistant tumor growth while enhancing enzalutamide sensitivity. Collectively, these findings highlight IGFBP3-mediated SphK1 signaling as a critical mediator of enzalutamide resistance and suggest that targeting the IGFBP3/SphK1/S1P axis represents a promising therapeutic strategy to overcome resistance in advanced prostate cancer.
Source: Molecular Cancer Therapeutics
Authors: Amy R. Leslie, Shu Ning, Masuda Sharifi, Zachary A. Schaaf, James P. Maine, Wei Lou, Kristina D. Leslie, Chengfei Liu, Hongyu Xu, Alan P. Lombard, Hong-Wu Chen, Mamta Parikh, Marc Dall’Era, Allen C. Gao
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1270792364, G2133784298, Targeting AR variants in advanced prostate cancer, G5039608234, G666092094, Therapeutic targeting steroid sulfatase for advanced prostate cancer, G6955084610, G7943031083, Novel therapeutics dual targeting intracrine androgen synthesis and AR for advanced prostate cancer, Therapeutic targeting Wnt5A signaling for advanced prostate cancer, The UC Davis enhanced Molecular, Cellular, and Developmental Biology Training Program
OpenAlex ID: W4417030552