Exploiting the Mitochondrial Fox 03A/SIRT3 Complex in Cancer Therapy

Celestini, Valentina (2019). Exploiting the Mitochondrial Fox 03A/SIRT3 Complex in Cancer Therapy. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000e611


As other many transcription factors, FoxO family members are involved in several cellular processes, including proliferation, apoptosis, stress resistance and metabolism. Their activity is finely regulated by phosphorylation, acetylation and ubiquitination events, which are modulated by multiple signalling pathways. Through the combination of specific post-translational modifications, composing a unique “molecular FoxO code”, FoxO proteins modulate different physiological processes and pathological events, such as cancer.

Previously, a mitochondrial arm of the AMPK-FoxO3A axis, representing a mechanism sustaining the energy metabolism upon nutrient shortage, has been revealed in normal cells and tissues. Data collected during this project show that in metabolically stressed cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK pathways. These kinases phosphorylate Serine 12 and 30, respectively, on the FoxO3A N-terminal domain, which is required for FoxO3A recruitment to the mitochondrial surface. Upon translocation into the organelle, the N-terminal domain is cleaved by processing peptidases, and the released product reaches the mitochondrial matrix. Here, the cleaved form of FoxO3A binds to the mitochondrial DNA (mtDNA) and activates the transcription of the mitochondrial genes, to support mitochondrial metabolism and cell survival. Interestingly, it seems to be a cancer-specific mechanism. Moreover, in cancer cells treated with chemotherapeutic agents, accumulation of FoxO3A into the mitochondria promotes their survival in a MEK/ERK-dependent manner. Importantly, mitochondrial FoxO3A is required for apoptosis induction by Metformin. Elucidation of FoxO3A mitochondrial versus nuclear functions in cancer cell homeostasis might help devise novel therapeutic strategies to disable FoxO3A pro-survival activity selectively.

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