Rotenone adaptation promotes migration and invasion of p53-wild-type colon cancer through lipid metabolism.

Background: The association between mitochondrial dysfunction and multiple metabolic adaptations is increasingly being proven. We previously elucidated that mitochondrial complex I deficiency can promote glycolysis in mut-p53 SW480 cells. However, studies have revealed a phenotype with attenuated glycolysis but enhanced fatty acid oxidation (FAO) in invasive tumors. The interplay between complex I and FAO in carcinogenesis remains obscure.

Methods: The p53 wild-type RKO cells were exposed to rotenone over at least 2 months to acquire rotenone adaptation cells. Then the transwell invasion assays and expression of metabolic enzymes were first detected in rotenone adaptation cells to illustrate whether rotenone adaptation is correlated with the invasion and FAO. The levels of epithelial-to-mesenchymal transition (EMT)-related proteins and acetyl-CoA in rotenone adaptation cells treated with etomoxir (ETO) and acetate were evaluated to verify the role of CPT1A in regulating invasion. Finally, the levels of reactive oxygen species (ROS) were detected. Meanwhile, the invasiveness and histone acetylation levels of rotenone adaptation cells were observed after adding an ROS inhibitor (N-acetyl-L-cysteine NAC) to demonstrate the molecular connection between FAO and invasion during rotenone adaptation.

Results: We found long-term exposure to rotenone (a mitochondrial complex I inhibitor) led to EMT and high CPT1A expression in wt-p53 colon cancer. The inhibition of CPT1A suppressed the invasion and reduced histone acetylation, which was rescued by supplementing with acetate. Mechanistically, ROS is crucial for lipid metabolism remodeling.

Conclusion: Our study provides a novel understanding of the role of complex I in lipid reprogramming facilitating colon cancer invasion and metastasis.