Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions.
Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions.
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DOI：
10.1016/j.celrep.2022.110320
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发表时间：
2022-02-01
期刊：
影响因子：
8.8
通讯作者：
Tennant DA
中科院分区：
文献类型：
--
作者：
Westbrook RL;Bridges E;Roberts J;Escribano-Gonzalez C;Eales KL;Vettore LA;Walker PD;Vera-Siguenza E;Rana H;Cuozzo F;Eskla KL;Vellama H;Shaaban A;Nixon C;Luuk H;Lavery GG;Hodson DJ;Harris AL;Tennant DA
癌细胞增殖的需求以及不充分的血管生成反应导致肿瘤微环境中氧气供应不足。在线粒体内，氧是NADH的主要电子受体，其结果是通过三羧酸（TCA）循环活性和线粒体呼吸产生的还原电位在功能上相关联。由于合成代谢前体的有效合成需要三氯乙酸循环的氧化活性，因此肿瘤缺氧可能会导致增殖停止，而无需其他纠正氧化还原失衡的方法。我们发现，在缺氧条件下，线粒体吡咯啉5-羧酸还原酶1（PYCR 1）的活性增加，氧化NADH与脯氨酸的合成作为副产品。我们进一步表明，PYCR 1活性是通过允许持续的TCA循环活性来成功维持缺氧区域所必需的，并且其损失导致体内和3D培养中缺氧显著增加，导致广泛的细胞死亡。低氧条件下通过PYCR 1的脯氨酸合成增加。低氧条件下PYCR 1活性通过NADH氧化支持TCA循环功能。表明当氧受限时，通过PYCR 1从谷氨酰胺合成脯氨酸支持NADH氧化。因此，PYCR 1代表了在缺氧中再生NAD+的氧非依赖性手段，支持持续的氧化TCA循环活性。肿瘤中PYCR 1的缺失导致缺氧增加、细胞活力降低和坏死。
The demands of cancer cell proliferation alongside an inadequate angiogenic response lead to insufficient oxygen availability in the tumor microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing potential produced through tricarboxylic acid (TCA) cycle activity and mitochondrial respiration are functionally linked. As the oxidizing activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance. We show that in hypoxic conditions, mitochondrial pyrroline 5-carboxylate reductase 1 (PYCR1) activity is increased, oxidizing NADH with the synthesis of proline as a by-product. We further show that PYCR1 activity is required for the successful maintenance of hypoxic regions by permitting continued TCA cycle activity, and that its loss leads to significantly increased hypoxia in vivo and in 3D culture, resulting in widespread cell death. Proline synthesis through PYCR1 is increased in low-oxygen conditions PYCR1 activity in hypoxia supports TCA cycle function through NADH oxidation PYCR1 is required for maintenance of hypoxic tumor regions Westbrook et al. show that proline synthesis from glutamine through PYCR1 supports NADH oxidation when oxygen is limited. PYCR1 therefore represents an oxygen-independent means of regenerating NAD+ in hypoxia, supporting continued oxidative TCA cycle activity. Loss of PYCR1 in tumors results in increased hypoxia, reduced cell viability, and necrosis.
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影响因子：
3.7
作者：
Frezza C;Zheng L;Tennant DA;Papkovsky DB;Hedley BA;Kalna G;Watson DG;Gottlieb E
通讯作者：
Gottlieb E
DOI：
10.1126/science.abd5491
发表时间：
2021-05-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Zhu J;Schwörer S;Berisa M;Kyung YJ;Ryu KW;Yi J;Jiang X;Cross JR;Thompson CB
通讯作者：
Thompson CB
影响因子：
5.7
作者：
Scott, Gary K.;Yau, Christina;Benz, Christopher C.
通讯作者：
Benz, Christopher C.
影响因子：
7.4
作者：
Krishnan, Navasona;Dickman, Martin B.;Becker, Donald F.
通讯作者：
Becker, Donald F.
影响因子：
--
作者：
Ivascu, Andrea;Kubbies, Manfred
通讯作者：
Kubbies, Manfred