Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions

Westbrook, Rebecca L.; Bridges, Esther; Roberts, Jennie; Escribano-Gonzalez, Cristina; Eales, Katherine L.; Vettore, Lisa; Walker, Paul D.; Vera-Sigüenza, Elías; Rana, Himani; Cuozzo, Federica; Eskla, Kattri‐Liis; Vellama, Hans; Shaaban, Abeer M.; Nixon, Colin; Luuk, Hendrik; Lavery, Gareth G.; Hodson, David J.; Harris, Adrian L.; Tennant, Daniel A.

doi:10.1016/j.celrep.2022.110320

Cited by 44 publications

(33 citation statements)

References 30 publications

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“… 24 Additionally, small molecule inhibitors of PYCR1 have been shown to impair the spheroidal growth of MCF10A H-RAS V12 breast cancer cells 25 and proliferation of myelogenous erythroleukemic K562 and epithelial breast cancer MDA-MB-231 cell lines. 26 Recent therapeutic studies have shown that silencing of PYCR1 reduces the progression and proliferation of the cancer cells 27 , 28 and leads to the induction of apoptosis. 11 Increased apoptosis with loss of PYCR1 has also been reported in other diseases such as autosomal recessive cutis laxa.…”

Section: Discussionmentioning

confidence: 99%

“… 37 PYCR1 was also shown recently to have a critical role in tumor cell growth by supporting redox homeostasis and the TCA cycle under hypoxic conditions. 27 Future work that examines whether the PYCR T171M variant reshapes proline metabolism in a way that favors cancer cell growth is needed to test this possibility.…”

Section: Discussionmentioning

confidence: 99%

“…It is proposed that PYCR1 provides an alternative source of NAD + that supports the TCA cycle when respiratory chain activity is low, thus ultimately promoting cancer cell progression . PYCR1 was also shown recently to have a critical role in tumor cell growth by supporting redox homeostasis and the TCA cycle under hypoxic conditions . Future work that examines whether the PYCR T171M variant reshapes proline metabolism in a way that favors cancer cell growth is needed to test this possibility.…”

Section: Discussionmentioning

confidence: 99%

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Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1

et al. 2023

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Pyrroline-5-carboxylate reductase (PYCR) is a proline biosynthetic enzyme that catalyzes the NAD(P)H-dependent reduction of Δ 1 -pyrroline-5-carboxylate (P5C) to proline. Humans have three PYCR isoforms, with PYCR1 often upregulated in different types of cancers. Here, we studied the biochemical and structural properties of the Thr171Met variant of PYCR1, which is found in patients with malignant melanoma and lung adenocarcinoma. Although PYCR1 is strongly associated with cancer progression, characterization of a PYCR1 variant in cancer patients has not yet been reported. Thr171 is conserved in all three PYCR isozymes and is located near the P5C substrate binding site. We found that the amino acid replacement does not affect thermostability but has a profound effect on PYCR1 catalytic activity. The k cat of the PYCR1 variant T171M is 100-to 200-fold lower than wild-type PYCR1 when P5C is the variable substrate, and 10-to 25-fold lower when NAD(P)H is varied. A 1.84 Å resolution X-ray crystal structure of T171M reveals that the Met side chain invades the P5C substrate binding site, suggesting that the catalytic defect is due to steric clash preventing P5C from achieving the optimal pose for hydride transfer from NAD(P)H. These results suggest that any impact on PYCR1 function associated with T171M in cancer does not derive from increased catalytic activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1

et al. 2023

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“…The amino acid proline is a polyfunctional compound. In addition to osmolytic, рroline performs other interrelated functions: membrane-protective, chaperone and antioxidant (Kovács et al, 2012;Kolupaev et al, 2014;Yan et al, 2021;Westbrook et al, 2022). There are few studies on the involvement of proline in moss stress reactions.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of carbohydrates and activity of the antioxidant system in mosses on a post-technogenic salinized territory

Kyyak

2022

Regul. Mech. Biosyst.

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Adaptive physiological and biochemical reactions of mosses Didymodon rigidulus Hedw., Barbula unguiculata Hedw. and Brachythecium campestre (Müll. Hal.) Schimp. to salt stress have been investigated from the territory of the tailings storage of the Stebnyk Mining and Chemical Enterprise “Polymineral” (Lviv region, Ukraine). The peculiarities of carbohydrate metabolism in mosses under salinity conditions have been studied. The content of soluble carbohydrates and proline, the antioxidant activity, the content of ascorbate and reduced glutathione as well as the activity of enzymes of their metabolism – ascorbate peroxidase and glutathione reductase at the initial stages of the stress (salt shock) and prolonged stress exposure (salt stress) have been evaluated. It has been found that the increase of α-amylase activity, enhancement of the hydrolysis of starch and the increase of the concentration of soluble carbohydrates under salt stress were the reactions of the studied species of mosses. It has been established that there was an increase in the concentration of soluble carbohydrates by 1.2–1.5 times in moss shoots under salinity conditions, compared with plants from the background area (vicinity of Stebnyk). Experimental studies have shown that under salinity conditions sucrose dominates in the pool of soluble carbohydrates (59.0–79.5% of the total sugars content). The sucrose content was 1.5–2.0 times higher in the plants B. unguiculata and D. rigidulus from the highly saline area of the tailings storage. It has been indicated that under stress conditions constitutive adaptive mechanisms are more expressed in resistant moss species, and plants with a lower level of resistance adapt to the stressor, mainly due to induced protective systems. Experimental studies have shown that plants B. unguiculata and D. rigidulus, which are resistant to abiotic stressors, have a high constitutive pool of soluble carbohydrates both at the beginning of the experiment and under prolonged exposure of the salt stress. In the shoots of the sensitive moss B. campestre the stress-induced character of the sugars accumulation has been revealed. The accumulation of proline in mosses cells under salt stress depended on their species characteristics. The stress-induced accumulation of proline can be considered as a part of the bryophytes’ protective system, but this osmolyte does not play a key role in the formation of the mosses’ resistance to salt stress. Obviously, soluble carbohydrates are the main osmolytes in the moss cells. It has been found that resistant moss species have a high constitutive antioxidant status, while in the sensitive moss B. campestre the increase in the antioxidant activity occurred during prolonged salt stress, which may indicate its induced nature. It has been shown that the resistant mosses B. unguiculata and D. rigidulus have 3–4 times higher levels of glutathione and ascorbate content and 1.6–2.5 times higher activity of enzymes of their metabolism – glutathione reductase and ascorbate peroxidase, compared to plants of the less tolerant moss species B. campestre, which provided reduction of the lipid peroxidation process in plasma membranes and decreased the content of TBA-active products under stress.

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“…Nevertheless, proline synthesis enzymes are frequently upregulated in cancer ( 161 , 162 ) and endogenous proline synthesis supports cancer cell proliferation. While exogenous proline can be obtained from the TME, de novo proline synthesis in cancer cells is required to maintain cellular redox state via NADH recycling by 5-carboxylate reductase 1 (PYCR1) ( 163 ). On the other hand, proline degradation by proline dehydrogenase (PRODH) sustains breast cancer metastases and promotes epithelial to mesenchymal transition in lung cancer, effects sensitive to PRODH inhibitor L-tetrahydro-2-furoic acid (L-THFA) ( 164 , 165 ).…”

Section: Amino Acidsmentioning

confidence: 99%

Effects of metabolic cancer therapy on tumor microenvironment

et al. 2022

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Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly – clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.

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Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions

Abstract: Highlights d Proline synthesis through PYCR1 is increased in low-oxygen conditions d PYCR1 activity in hypoxia supports TCA cycle function through NADH oxidation d PYCR1 is required for maintenance of hypoxic tumor regions

Cited by 44 publications

References 30 publications

Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1

Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1

Metabolism of carbohydrates and activity of the antioxidant system in mosses on a post-technogenic salinized territory

Effects of metabolic cancer therapy on tumor microenvironment

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Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions

Abstract: Highlights d Proline synthesis through PYCR1 is increased in low-oxygen conditions d PYCR1 activity in hypoxia supports TCA cycle function through NADH oxidation d PYCR1 is required for maintenance of hypoxic tumor regions

Cited by 44 publications

References 30 publications

Functional Impact of a Cancer-Related Variant in Human Δ1-Pyrroline-5-Carboxylate Reductase 1

Functional Impact of a Cancer-Related Variant in Human Δ1-Pyrroline-5-Carboxylate Reductase 1

Metabolism of carbohydrates and activity of the antioxidant system in mosses on a post-technogenic salinized territory

Effects of metabolic cancer therapy on tumor microenvironment

Contact Info

Product

Resources

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Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1

Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1