Functional role of pentose phosphate pathway and glutamine in cancer cell metabolism

Abstract

[eng] In this thesis, tumor metabolic reprogramming has been exploited in order to propose new targets in cancer treatment. On one hand, we explored the pentose phosphate pathway (PPP) enzymes as putative therapeutic targets against breast and colon cancer. We observed that inhibition of ox-PPP enzymes G6PD in colon cancer cells and 6PGD in breast cancer cells halted cell prolifertion, resulted in cell cycle arrest and apoptosis. We also demosntrated that in colon cancer cells G6PD is strongly regulated by the glutamine availability mediated by NRF2 transcription factor. Moreover, 6PGD inhibition decreased mammosphere formation capacity of breast cancer cells implying that stem cell characteristics of breast cancer cells were altered by 6PGD inhibition. Besides that, 6PGD inhibition also altered the central carbon metabolism of breast cancer cells leading to decreased glucose consumption and increased glutamine consumption. Observing that both pathways are deeply related to glutamine metabolism, we decided to investigate the metabolic network adaptations that breast cancer cells undergo when the glutamine is scarce. Knowing that hypoxic conditions are common features of tumor microenvironments, we also investigated the characterization of a hypoxia mimicking condition which leads to defective mitochondria. In fact, in these two conditions, we produced huge amount of transcriptomics, metabolomics and fluxomics data in order to produce a genome scale metabolic model (GSMM) combining multi-omics data in the frame of a European project which helps us to understand the regulation of metabolic alterations in breast cancer cells. While produced data is to be used in production of GSMM, we also took advantage of the data to study the metabolic adaptations that breast cancer cells undergo in the deprivation of glutamine or when mitochondria are defected. We propose that increased pyruvate cycle with glutamine deprivation and increased reductive carboxylation with not fully functional mitochondria could be targeted in combination therapies to fight against cancer. All in all, besides showing the importance of metabolism in cancer cell proliferation and survival, the results presented in this study also highlights the importance of Systems Biology approaches to understand the molecular mechanisms underlying complex multifactorial diseases in order to develop new potential therapeutic targets.