A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process.
A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process.
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DOI：
10.1186/2049-3002-2-4
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发表时间：
2014-03-10
影响因子：
5.9
通讯作者：
Zachar Z
中科院分区：
文献类型：
--
作者：
Stuart SD;Schauble A;Gupta S;Kennedy AD;Keppler BR;Bingham PM;Zachar Z
靶向肿瘤细胞代谢被认为是肿瘤化疗的一个有前途的领域。此外，肿瘤细胞的氧化还原代谢也发生了系统性的改变。确实，有越来越多的理由相信，氧化还原控制代谢的肿瘤特异性改变将是理解和攻击恶性肿瘤的核心。我们在这里报道，脂酸类似物CPI-613通过氧化还原机制选择性地攻击肿瘤细胞中使用脂酸的代谢酶- α -酮戊二酸脱氢酶（KGDH）。CPI-613对肿瘤细胞中KGDH功能的抑制作用强、快速、选择性。此外，CPI-613在肿瘤细胞线粒体中诱导了相应的快速、强大的氧化还原信号。该信号与KGDH的氧化还原修饰（包括广泛的谷胱甘肽酶化和脂酸硫酰酶的氧化还原阻断）相关，与KGDH失活相关。这种肿瘤特异性线粒体氧化还原调节信号的来源不是电子传递复合物（I或III），而主要或全部是脱氢酶的E3（二氢脂酰胺脱氢酶）成分，包括KGDH。最后，我们证明KGDH活性（在肿瘤细胞中）受到氧化还原调节，正如预期的那样，如果肿瘤特异性氧化还原过程（auto）调节KGDH。我们的数据表明，脂酸类似物CPI-613攻击肿瘤细胞中KGDH活性的氧化还原控制，可能是通过调节通常控制肿瘤细胞KGDH活性的现有脂酸敏感变弹性过程。CPI-613的KGDH效应，加上其先前报道的，对其他主要的，使用线粒体代谢酶，丙酮酸脱氢酶的脂酸的机制不同（非氧化还原）作用，表明该药物同时攻击肿瘤细胞代谢调节的多个中心基本成分。
Targeting cancer cell metabolism is recognized as a promising arena for development of cancer chemotherapeutics. Moreover, redox metabolism is also systematically altered in tumor cells. Indeed, there is growing reason to believe that tumor-specific alteration of redox control of metabolism will be central to understanding and attacking malignancy. We report here that lipoate analog CPI-613 attacks a gate-keeping, lipoate-using metabolic enzyme, alpha-ketoglutarate dehydrogenase (KGDH), by a redox mechanism selectively in tumors cells. CPI-613 inhibited KGDH function strongly and rapidly, selectively in tumor cells. Moreover, CPI-613 induced a correspondingly rapid, powerful redox signal in tumor cell mitochondria. This signal was associated with redox modification of KGDH (including extensive enzyme glutathionylation and redox blockage of enzyme lipoate sulfhydryls), correlating with KGDH inactivation. The source of this tumor-specific mitochondrial redox modulatory signal was not electron transport complexes (I or III), but was largely or entirely the E3 (dihydrolipoamide dehydrogenase) component of dehydrogenases, including KGDH. Finally, we demonstrated that KGDH activity was redox regulated (in tumor cells), as expected if a tumor-specific redox process (auto)regulates KGDH. Our data demonstrate that lipoate analog CPI-613 attacks redox control of KGDH activity in tumor cells, perhaps by modulation of an existing lipoate-sensitive allosteric process normally governing tumor cell KGDH activity. Together with its previously reported, mechanistically distinct (non-redox) effects on the other major, lipoate-using mitochondrial metabolic enzyme, pyruvate dehydrogenase, CPI-613’s KGDH effects indicate that this agent simultaneously attacks multiple central, essential components of tumor cell metabolic regulation.