Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells
Stefano Bartesaghi,Vincenzo Graziano,Sara Galavotti,Nick V. Henriquez,Joanne Betts,Jayeta Saxena,Valentina Minieri,A Deli,Anna Karlsson,L. Miguel Martins,Melania Capasso,Pierluigi Nicotera,Sebastian Brandner,Vincenzo De Laurenzi,Paolo Salomoni +14 more
TLDR
In this paper, the p53 tumor suppressor is genetically inactivated in a large proportion of high grade glioma (HGG) cases, which is caused by increased reactive oxygen species and associated oxidative DNA damage.Abstract:
Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.read more
Citations
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Evolutionary Determinants of Cancer
TL;DR: An evolutionary perspective may provide a clearer understanding of how cancer clones develop robustness and why, for us as a species, risk is now off the scale.
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Metabolic Reprogramming in Glioma
TL;DR: The current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism are presented.
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Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival.
Edoardo Gaude,Christian Frezza +1 more
TL;DR: It is found that cancers undergo a tissue-specific metabolic rewiring, which converges towards a common metabolic landscape, and suppression of mitochondrial genes is identified as a key metabolic signature of metastatic melanoma and renal cancer, and metastatic cell lines.
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Redox Signaling by Reactive Electrophiles and Oxidants
TL;DR: This Review reflects on five aspects critical for understanding how nature harnesses these noncanonical post-translational modifications to coordinate distinct cellular activities: specific players and their generation, physicochemical properties, mechanisms of action, methods of interrogation, and functional roles in health and disease.
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Cancer as a mitochondrial metabolic disease.
TL;DR: Evidence from nuclear cytoplasm transfer experiments that relate to the origin of cancer is reviewed, finding that the evidence is difficult to reconcile with the somatic mutation theory, but consistent with the notion that cancer is primarily a mitochondrial metabolic disease.
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