The study of RAS-induced metabolic reprogramming and the role of the pentose phosphate pathway in tumor metabolism

摘要: The present doctoral thesis is focused on the metabolic adaptations induced by oncogene activation as well potential role of network antitumor therapy. Over last years, it has emerged a renewed interest in field metabolism, particularly cancer metabolism. Great efforts have been association mutated oncogenes or tumor suppressor genes and profiles, search dependencies that offer new avenues for treatment. pursuit discovering alterations which cells rely represented cornerstone this interesting discipline. Thus, part recent promising scientific current intended to shed light accompanying mutation pathways might be therapeutic future. Hence, objectives can divided into two specific aims: i) analysis reprogramming RAS oncogenic using stable transfected cell lines with copies K-RAS H-RAS ii) validation pentose phosphate pathway target exploration its within metabolism colon breast models. according proposed objectives, main conclusions obtained are follow: 1. study flux distribution combination control performed analyzing solely sign fixed-sign coefficients, reliable approach identify key enzymes involved reprogramming. use methodology allowed us an increase glycolysis PPP fluxes features KRAS-induced propose G6PD, PK LDH responsible transition. 2. reprograms glucose glutamine enhancing glycolytic mitochondrial Glutamine sustaining activated BJ-HRasV12, while glucose-derived carbons mitochondria primarily used fuel lipogenesis. Moreover, lipogenesis overactivated BJ-HRasV12 cells, more sensitive FAS inhibition than BJ cells. 3. G6PD enzyme signaling pathway. Nevertheless, seems dispensable proliferation survival BRAF-mutated HT29 line. Furthermore, connection between unveiled, overexpressed under glutamine-deprived conditions mechanism involving concomitantly ROS levels NRF2 induction. 4. important proliferation, regulation MCF7 However, exerts low over ribose synthesis through oxidative branch PPP. enhances flux, promotes lactate secretion increases consumption, maintain energy homeostasis, although not essential proliferation. 5. TKT but high nonoxidative impairment reduces consumption glutamine, homeostasis