Metastasis remains the foremost cause of death in cancer patients. Cells with metastasizing potentials are equipped to evade anoikis, a form of cell death resulting from cell detachment from extracellular matrix. Evasion of anoikis signals avails cells the ability to detach, migrate, and invade secondary sites, colonizing these sites thereby promote cancer metastasis. Cellular reprogramming has been identified as a crucial factor for tumor metastasis and yet to be fully explored. Our data showed upregulation in oxidative phosphorylation (OXPHOS) related genes in detached cells compared to adherent cells, suggesting that OXPHOS activity may enhance resistance to anoikis. Accordingly, treatment with metformin, a mitochondrial complex 1 inhibitor promoted anoikis in different cancer cells (cervical cancer - Hela, breast - MCF7, melanoma -B16F10 and Lewis Lungs carcinoma - LLC). Furthermore, metformin decreased spheroid formation, repressed ATP production, accumulated misfolded protein, and sensitized cells to anoikis via activation of caspase 3 and ROS production. More importantly, targeting OXPHOS with metformin inhibited pulmonary tumor metastasis, impaired lung nodules formation, and reduced lung weight in the B16F10 tumor model of balb/c nude mice. Collectively, our findings suggest therapeutic targeting of energy metabolism using metformin as a promising approach to enhance anoikis and attenuate tumor metastasis.

Citation Format: Funmilayo Oladunni Adeshakin, Guizhong Zhang, Adeleye O. Adeshakin, Xiaochun Wan. Blockade of oxidative phosphorylation by metformin promotes anoikis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2869.