Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells.
Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells.
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DOI：
10.1126/scisignal.2004761
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发表时间：
2014-04-01
影响因子：
7.3
通讯作者：
Ann DK
中科院分区：
文献类型：
--
作者：
Qiu F;Chen YR;Liu X;Chu CY;Shen LJ;Xu J;Gaur S;Forman HJ;Zhang H;Zheng S;Yen Y;Huang J;Kung HJ;Ann DK
自噬是对营养饥饿的主要分解代谢反应，并且是清除功能障碍或受损细胞器所必需的，但是过度的自噬可以是细胞毒性的或细胞生长抑制的，并且有助于细胞死亡。取决于参与分子生物合成的酶的丰度，细胞可以依赖于摄取外源营养物来提供这些分子。精氨琥珀酸合成酶1（ASS 1）是精氨酸生物合成的关键酶，其丰度在许多实体瘤中降低，使其对外部精氨酸耗竭敏感。我们证明，通过暴露于ADI-PEG 20（聚乙二醇化精氨酸脱亚胺酶）延长精氨酸饥饿诱导ASS 1缺陷型乳腺癌细胞的自噬依赖性死亡，因为这些细胞是精氨酸营养缺陷型（依赖于细胞外精氨酸的摄取）。事实上，当暴露于ADI-PEG 20或在没有精氨酸的情况下培养时，这些乳腺癌细胞在培养中死亡。精氨酸饥饿诱导线粒体氧化应激，损害线粒体的生物能量学和完整性。此外，精氨酸饥饿杀死乳腺癌细胞在体内和体外，只有当他们是自噬能力。因此，长期精氨酸饥饿诱导的致死性的一个关键机制是响应线粒体损伤而发生的细胞毒性自噬。最后，在149个随机乳腺癌生物样本中，超过60%的样本中，ASS 1丰度低或不存在，这表明患有此类肿瘤的患者可能是精氨酸饥饿治疗的候选人。
Autophagy is the principal catabolic response to nutrient starvation and is necessary to clear dysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic and contributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis, cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinate synthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solid tumors, making them sensitive to external arginine depletion. We demonstrated that prolonged arginine starvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependent death of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent on uptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed to ADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidative stress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killed breast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanism underlying the lethality induced by prolonged arginine starvation was the cytotoxic autophagy that occurred in response to mitochondrial damage. Last, ASS1 was either low in abundance or absent in more than 60% of 149 random breast cancer bio-samples, suggesting that patients with such tumors could be candidates for arginine starvation therapy.
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影响因子：
45.3
作者：
Ascierto, PA;Scala, S;Logan, TF
通讯作者：
Logan, TF
影响因子：
4.8
作者：
Bianchi, C;Genova, ML;Lenaz, G
通讯作者：
Lenaz, G
影响因子：
9
作者：
通讯作者：
--
影响因子：
11.8
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
通讯作者：
Nunnari, Jodi
影响因子：
2.9
作者：
Birrell JA;Hirst J
通讯作者：
Hirst J