Unravelling the effects of hypoxia on purine biosynthesis in cancer

Abstract

The purinosome is a dynamic metabolic complex composed of the six enzymes of the de novo purine biosynthesis that assembles in response to elevated purine demand. Its formation translates in an increase to the rate of the pathway in order to maintain the purine pool. This complex was first described to form in an artificially induced purine-depleted environment but later studies demonstrated its ability to form in pathological contexts, thus making the purinosome a promising therapeutic target to control purine synthesis. In various cancers, solid tumours often display hypoxic regions where oxygen deprivation induces a cellular response aiming at maintaining cell growth and proliferation, and contributes to the tumours resistance to treatments. In hypoxic cells, the heterodimeric transcription factor Hypoxia-Inducible Factor 1 (HIF-1) is responsible for the regulation of many target genes that ensure the response and adaptation of cancer cells to hypoxia. One of the most important adaptation mechanisms regulated by HIF is the metabolic reprogramming which supports the malignant phenotype of hypoxic tumours. As such, improving the current understanding of the metabolic adaptation to hypoxia is of high interest in order to further develop new therapeutic strategies to target hypoxic cancer cells. This work describes and investigates the formation of the purinosome complex in hypoxic cancer cells. Multiple cellular and biochemical approaches were used in order to characterise and understand the formation of the complex in low oxygen environments. The purinosome formation was found to be linked to HIF and to be modulated by various metabolic stimuli, thus indicating a link between the formation of the complex and its function. In contrast to its previously reported function in purine-depleted conditions, the hypoxic purinosome did not correlate with increased de novo synthesis of purines. This study lays the foundation for further investigations aiming at understanding the exact function of the purinosome in hypoxic cancer cells and raises the possibility that inhibiting purinosome formation in hypoxia might be of high therapeutic interest to specifically target hypoxic cancer cells