Fig. 8: FoxO3A represents a survival factor in metabolically stressed cancer cells. | Cell Death & Disease

Fig. 8: FoxO3A represents a survival factor in metabolically stressed cancer cells.

From: Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy

Fig. 8

Normal cells and tissues under metabolic stress require only the AMPK signal on S30 to direct FoxO3A into the mitochondria. It seems that ERK involvement in FoxO3A mitochondrial localization is exclusive to tumor cells, which reveals a critical difference between normal and cancer cells that could be exploited for cancer therapeutics. In metabolically stressed cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK, which phosphorylate serine 12 and 30, respectively, on FoxO3A N-terminal domain. Subsequently, FoxO3A is imported and cleaved to reach mitochondrial DNA, where it activates expression of the mitochondrial genome to support mitochondrial metabolism. In cancer cells treated with chemotherapeutic agents, accumulation of FoxO3A into the mitochondria promoted survival in a MEK/ERK-dependent manner, while mitochondrial FoxO3A was required for apoptosis induction by metformin

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