Enhancing of Nanocatalyst-Driven Chemodynaminc Therapy for Endometrial Cancer Cells Through Inhibition of PINK1/Parkin-Mediated Mitophagy

Abstract

Xiaodi Gong,1,* Xin Pu,2,* Jing Wang,1 Linlin Yang,1 Yunxia Cui,1 Lijuan Li,1 Xiao Sun,1 Jichang Liu,2 Jingfeng Bai,3 Yudong Wang1,4 1Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2State Key Laboratory of Chemical Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, People’s Republic of China; 3Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yudong WangDepartment of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of ChinaTel [phone]-18602Email [email protected] BaiBiomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of ChinaTel [phone]Email [email protected]: Iron-based nanomaterials have recently been developed as excellent and potent Fenton reagents to reactive oxygen species (ROS) during chemodynamic therapy (CDT). The performance of the materials, however, can be impaired by the intrinsic antioxidant defense mechanism in organisms, such as autophagy.Methods: The nanoscale metal-organic frameworks (nMOFs), nMIL-100 (Fe), were exploited and characterized. Also, the Fenton-like catalytic characteristics, anti-endometrial cancer (EC) effects and potential mechanisms of nMIL-100 (Fe) nanoparticles were investigated in vitro.Results: The synthesized nMIL-100 (Fe) nanocatalyst catalyzed hydroxyl radicals (·OH) production in the presence of hydrogen peroxide (H2O2) and simultaneously depleted intracellular glutathione (GSH). Combining with H2O2, nMIL-100 (Fe) nanoparticles exhibited enhanced cytotoxicity for EC cells, especially for progesterone treatment-insensitive KLE cells, probably due to relatively lower expression of the catalase gene. The accumulated ·OH initiated PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin-mediated cytoprotective mitophagy in turn to partially rescue ·OH-induced cell apoptosis. Furthermore, both pretreatments of EC cells with siRNA-mediated Parkin knockdown and Mdivi-1 (a mitophagy inhibitor) addition were sufficient to ensure nMIL-100 (Fe) synergizing with H2O2-induced oxidative damages.Conclusion: These results suggest that the degree of mitophagy should be taken into consideration to optimize therapeutic efficiency when developing ROS based-CDT for EC cancer therapies. Therefore, a nMIL-100 (Fe)-guided, elevated ROS and overwhelmed mitophagy-mediated therapeutic strategy may have greater promise for EC therapy compared with current treatment modalities.Keywords: mitophagy, chemodynamic therapy, metal-organic frameworks, nanocatalyst, endometrial cancer

Keywords

• mitophagy
• chemodynamic therapy
• metal-organic frameworks
• nanocatalyst
• endometrial cancer