Borzacchiello, Domenica (2021) Metabolic control of tumor growth by mitochondrial A-KINASE anchor protein 1 (AKAP1). [Tesi di dottorato]

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Mitochondria are powerhouses present in all eukaryotic cells that play a fundamental role in energy production, survival and metabolism. In cancer cells, mitochondria provide the building blocks for the biogenesis of cellular organelles, cytoskeleton and membranes, and supply all the metabolic needs for cancer growth and spreading in vivo. AKAP1 is a scaffold protein that integrates and focus cAMP and src signaling on mitochondria, regulating protein synthesis, organelle biogenesis, oxidative metabolism and cell survival. During my thesis, I analyzed the mechanisms controlling the expression of AKAP1 in cancer cells and the role of this anchor protein in the control of metabolic pathways and cancer growth. I found that transcription and accumulation of AKAP1 are induced by the Myc proto-oncogene and by steroid hormones. I detected high levels of AKAP1 in a wide variety of high-grade human cancer tissues and cells, including prostate cancer, breast cancer and glioblastoma (GBM). I demonstrated that AKAP1 is required for mTOR pathway, oxidative metabolism and cancer growth, both in vitro and in vivo. Interestingly, I discovered a link between DNA damage pathways and AKAP1. In particular, I found that, in course of DNA damage, AKAP1 is phosphorylated by ATM/ATR kinase at its PKA binding domain. Phosphorylation of AKAP1 by ATM inhibits PKA targeting to mitochondria and downregulates oxidative metabolism. These data disclose a previously unrecognized role of AKAP1 in mTOR pathway and cancer growth AKAP1 and identify AKAP1 as a novel biologically relevant target of the DNA damage pathways.

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