Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel‒Lindau tumor suppressor‐mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation
Fuyan Xu,
Jiao Li,
Min Ai,
Tingting Zhang,
Yue Ming,
Cong Li,
Wenchen Pu,
Yang Yang,
Zhang Li,
Yucheng Qi,
Xiaomin Xu,
Qingxiang Sun,
Zhu Yuan,
Yong Xia,
Yong Peng
Affiliations
Fuyan Xu
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Jiao Li
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Min Ai
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Tingting Zhang
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Yue Ming
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Cong Li
Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Wenchen Pu
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Yang Yang
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Zhang Li
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Yucheng Qi
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Xiaomin Xu
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Qingxiang Sun
Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Zhu Yuan
Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Yong Xia
Rehabilitation Medicine Center State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Yong Peng
Laboratory of Molecular Oncology Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
Abstract Melanoma's high metastatic potential, especially to the brain, poses significant challenges to patient survival. The blood‒brain barrier (BBB) is a major obstacle to the effective treatment of melanoma brain metastases. We screened antipsychotic drugs capable of crossing the BBB and identified penfluridol (PF) as the most active candidate. PF reduced melanoma cell viability and induced apoptosis. In animal models, PF effectively inhibited melanoma growth and metastasis to the lung and brain. Using immunoprecipitation combined with high‐resolution mass spectrometry, and other techniques such as drug affinity responsive target stability, we identified CIP2A as a direct binding protein of PF. CIP2A is highly expressed in melanoma and its metastases, and is linked to poor prognosis. PF can restore Protein Phosphatase 2A activity by promoting CIP2A degradation, thereby inhibiting several key oncogenic pathways, including AKT and c‐Myc. Additionally, von Hippel‒Lindau (VHL) is the endogenous E3 ligase for CIP2A, and PF enhances the interaction between VHL and CIP2A, promoting the ubiquitin‒proteasome degradation of CIP2A, thereby inhibiting melanoma growth and metastasis. Overall, this study not only suggests PF's potential in treating melanoma and its brain metastases but also highlights CIP2A degradation as a therapeutic strategy for melanoma.
