Curcumin-mediated photodynamic action disturbs TOM70-depedent MIC60 import to damage mitonchondria against breast cancer

The regulation of mitochondrial membrane proteins is of crucial significance for breast Cancer therapy. TOM70, which located in mitochondria outer membrane, could import MIC family molecules to preserve mitochondrial homeostasis. However, there are few agents targeting TOM70. Therein, the effects of curcumin and it's mediated photodynamic therapy (PDT) on the TOM70 and mitochondrial function for breast Cancer treatment were investigated. The 4 T1 and MDA-MB-231 cells were utilized as the breast Cancer cells. The 4 T1 cell-bearing mice were constructed as the breast Cancer animal model. The anti-cancer efficacy was validated using the CCK-8, Annexin-V/PI staining, colony formation. The associated molecules were detected by Western blots (WB), RT-qPCR, and Immunohistochemistry (IHC). The target was verified by molecular docking, CETSA, and DARTS. The mitochondrial proteins and DNA were extracted for the MIC60 and mtDNA damage detection. Curcumin treatment showed poor efficacy in the breast Cancer model, as characterized by cell viability, Apoptosis, proliferation of breast Cancer cells, and the growth of tumor grafts in mice. However, curcumin-mediated PDT inhibited breast Cancer in vitro and in vivo. Further exploration identified curcumin bond to TOM70, which is highly expressed in breast Cancer, thereby activating it. But curcumin-induced PDT inactivated TOM70 through generated Reactive Oxygen Species (ROS), which in turn interfered with the binding of MIC60 and its translocation into mitochondria. Curcumin-triggered PDT led to severe mitochondrial damage compared with the curcumin treatment, which could be blocked by the N-Acetylcysteine (NAC). Additional TOM70 rescue dampened curcumin PDT-mediated mitochondrial damage and anti-breast Cancer efficacy. To summarize, the present research identifies curcumin-induced PDT inactivated TOM70, thereby attenuating MIC60 import, leading to mitochondrial damage against breast Cancer. We propose a novel approach to tumor treatment through the regulation of mitochondrial membrane proteins using the phytomedicine-driven PDT.

Breast cancer; Curcumin; MIC60; Mitochondrial damage; Photodynamic therapy (PDT); TOM70.