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Unravelling the effects of hypoxia on purine biosynthesis in cancer

Unravelling the effects of hypoxia on purine biosynthesis in cancer
Unravelling the effects of hypoxia on purine biosynthesis in cancer
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.
University of Southampton
Doigneaux, Cyrielle
9f8adf0b-137e-4642-8cfc-e7e0e556d4b0
Doigneaux, Cyrielle
9f8adf0b-137e-4642-8cfc-e7e0e556d4b0
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Doigneaux, Cyrielle (2020) Unravelling the effects of hypoxia on purine biosynthesis in cancer. University of Southampton, Doctoral Thesis, 224pp.

Record type: Thesis (Doctoral)

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.

Text
Cyrielle Doigneaux-thesis-for award
Restricted to Repository staff only until 20 April 2023.
Available under License University of Southampton Thesis Licence.
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PTD with approval
Restricted to Repository staff only

More information

Published date: March 2020

Identifiers

Local EPrints ID: 447233
URI: http://eprints.soton.ac.uk/id/eprint/447233
PURE UUID: 931069b3-2187-44b6-b02c-20ba49b81e0b
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

Catalogue record

Date deposited: 05 Mar 2021 17:30
Last modified: 06 Mar 2021 02:39

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Contributors

Author: Cyrielle Doigneaux
Thesis advisor: Ali Tavassoli ORCID iD

University divisions

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