Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis

Hollinshead, Kate E.R.; Munford, Haydn; Eales, Katherine L.; Bardella, Chiara; Li, Chunjie; Escribano-Gonzalez, Cristina; Thakker, Alpesh; Nonnenmacher, Yannic; Kľučková, Katarína; Jeeves, Mark; Murren, Robert; Cuozzo, Federica; Ye, Dan; Laurenti, Giulio; Zhu, Wei; Hiller, Karsten; Hodson, David J.; Hua, Wei; Tomlinson, Ian; Ludwig, Christian; Mao, Ying; Tennant, Daniel A.

doi:10.1016/j.celrep.2018.02.084

Cited by 73 publications

(72 citation statements)

References 30 publications

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“…Finally, proline synthesis by pyrroline-5-carboxylate reductase (PYCR) from glutamine can also help regulate redox balance by regenerating NAD þ , which in turn may promote TCA cycling (34). Accordingly, we found that statin treatment robustly increased proline synthesis from glutamine ( Fig.…”

Section: Statin-induced Reduction In Coq Levels Causes Elevated Ros Amentioning

confidence: 77%

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

et al. 2020

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Statins are widely prescribed inhibitors of the mevalonate pathway, acting to lower systemic cholesterol levels. The mevalonate pathway is critical for tumorigenesis and is frequently upregulated in cancer. Nonetheless, reported effects of statins on tumor progression are ambiguous, making it unclear whether statins, alone or in combination, can be used for chemotherapy. Here, using advanced mass spectrometry and isotope tracing, we showed that statins only modestly affected cancer cholesterol homeostasis. Instead, they significantly reduced synthesis and levels of another downstream product, the mitochondrial electron carrier coenzyme Q, both in cultured cancer cells and tumors. This compromised oxidative phosphorylation, causing severe oxidative stress. To compensate, cancer cells upregulated antioxidant metabolic pathways, including reductive carboxylation, proline synthesis, and cystine import. Targeting cystine import with an xCT transporterlowering MEK inhibitor, in combination with statins, caused profound tumor cell death. Thus, statin-induced ROS production in cancer cells can be exploited in a combinatorial regimen. Significance: Cancer cells induce specific metabolic pathways to alleviate the increased oxidative stress caused by statin treatment, and targeting one of these pathways synergizes with statins to produce a robust antitumor response. See related commentary by Cordes and Metallo, p. 151

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Section: Statin-induced Reduction In Coq Levels Causes Elevated Ros Amentioning

confidence: 77%

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

et al. 2020

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“…Proline metabolism in cancer cells has been recently recognised as a tumour vulnerability and potential target for therapy 70 . Cancer cells with low levels of proline synthesis enzymes or under nutrient limiting conditions are vulnerable to proline shortage 58,61 and proline synthesis is important to maintain mitochondrial redox homeostasis in cancer cells with IDH1 oncogenic mutations 71 .…”

Section: Discussionmentioning

confidence: 99%

PYCR1-dependent proline synthesis in cancer-associated fibroblasts is required for the deposition of pro-tumorigenic extracellular matrix

Kay

Paterson

Domingo

et al. 2020

Preprint

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The extracellular matrix (ECM) is the central driver of the desmoplastic reaction that fosters cancer aggressiveness. Cancer associated fibroblasts (CAFs) are the major source of ECM in tumours, thus being the optimal target to limit deposition of pro-tumourigenic ECM to oppose cancer. CAFs are metabolically active cells, however, how they support the biosynthetic requirements of producing ECM, and whether this can be targeted to influence tumour progression has not been investigated.We found that the pyruvate dehydrogenase kinase 2 (PDK2), a major inhibitor of the pyruvate dehydrogenase complex (PDC), is highly downregulated in CAFs and in the tumour stroma, when compared to normal fibroblasts. As consequence, PDC is more activated and generates acetyl-CoA, which elicits an epigenetic reprogramming through the histone acetyl transferase P300/CBP. This epigenetic reprogramming drives increased ECM production through increasing transcription of collagen genes and proline synthesis. We found that increased proline availability is necessary to support the biosynthetic requirements that follow the epigenetic reprogramming, for the translation of collagen to make abundant ECM. Targeting the rate-limiting enzyme for proline synthesis, pyrroline-5-carboxylate reductase 1 (PYCR1), in CAFs was sufficient to limit collagen deposition and hamper tumour growth. In conclusion, ECM production in CAFs is under strict metabolic control, and our results warrant considering targeting proline synthesis to normalise ECM production in tumours and possibly other diseases involving collagen production, such as fibrosis.

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“…c-Myc and PI3K upregulate proline synthesis [43]. Enhanced proline synthesis by PYCR, supporting mitochondrial redox homeostasis, was reported in an oligodendroglioma cell line with an IDH1 mutation [44]. Following synthesis, proline may be catabolized by the proline oxidase (proline dehydrogenase; POX/PRODH), a putative tumor suppressor.…”

Section: Glutamine Addiction In Gliomasmentioning

confidence: 92%

Targeting Glutamine Addiction in Gliomas

Obara-Michlewska

Szeliga

2020

Cancers

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The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas.

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Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis

Cited by 73 publications

References 30 publications

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

PYCR1-dependent proline synthesis in cancer-associated fibroblasts is required for the deposition of pro-tumorigenic extracellular matrix

Targeting Glutamine Addiction in Gliomas

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