Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer.
Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer.
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作者：
线粒体，通常被称为“细胞的发电站”，产生所有细胞过程所需的大部分能量。线粒体还为多种功能提供平台，包括构建必需的大分子（核苷酸，蛋白质和脂质），细胞信号传导，解毒和细胞命运控制。研究表明，线粒体功能在乳腺癌中被广泛重新编程，以促进肿瘤进展。因此，靶向线粒体是目前乳腺癌研究的重点之一。超过1000种蛋白质参与线粒体功能。称为ClpP的线粒体蛋白酶在线粒体蛋白质质量控制中起着核心作用。最近，ClpP激动剂已经成为一类新的靶向药物。过度活化ClpP诱导ClpP底物的不受控制但选择性的降解，并破坏线粒体功能，导致乳腺癌细胞的生长抑制，而对非恶性细胞没有不利影响。ClpP激动剂的独特特性和作用机制为乳腺癌治疗提供了新的机会。乳腺癌是世界范围内最常见的恶性肿瘤，也是女性癌症死亡的主要原因。尽管最近开发了包括靶向疗法和免疫疗法在内的新疗法，但三阴性乳腺癌仍然是乳腺癌的侵袭性形式，因此需要改进的治疗。近几十年来，越来越清楚的是，乳腺癌具有由线粒体控制的代谢可塑性。大量的研究提供了线粒体对乳腺癌进展至关重要的证据。乳腺癌中的线粒体被广泛重新编程，以增强肿瘤生长所需的能量产生和大分子生物合成。在这篇综述中，我们将讨论目前对线粒体在乳腺癌中的作用的理解，并阐明为什么线粒体是一个合理的治疗靶点。然后，我们将概述在乳腺癌中使用靶向药物的地位，并强调ClpP激动剂作为新兴的靶向药物具有独特的作用机制。我们还说明了可能的药物组合策略和挑战，在未来的乳腺癌诊所。
Mitochondria, often called “the powerhouse of the cell”, generate most of the energy required for all cellular processes. Mitochondria also provide a platform for multiple functions, including building essential macromolecules (nucleotides, proteins, and lipids), cell signaling, detoxification, and cell fate control. Studies have demonstrated that mitochondrial function is widely reprogrammed in breast cancers to promote tumor progression. Therefore, targeting mitochondria is currently one of the focal points in breast cancer research. Over 1000 proteins are involved with mitochondrial functions. The mitochondrial protease called ClpP plays a central role in mitochondrial protein quality control. Recently, ClpP agonists have emerged as a novel class of mitochondria-targeting drugs. Hyperactivating ClpP induces uncontrolled, but selective, degradation of ClpP substrates and disrupts mitochondrial functions, leading to growth inhibition of breast cancer cells, without adverse effect in non-malignant cells. The unique characteristics and mechanism of action of ClpP agonists provide new opportunities in breast cancer treatment. Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer mortality in women. Despite the recent development of new therapeutics including targeted therapies and immunotherapy, triple-negative breast cancer remains an aggressive form of breast cancer, and thus improved treatments are needed. In recent decades, it has become increasingly clear that breast cancers harbor metabolic plasticity that is controlled by mitochondria. A myriad of studies provide evidence that mitochondria are essential to breast cancer progression. Mitochondria in breast cancers are widely reprogrammed to enhance energy production and biosynthesis of macromolecules required for tumor growth. In this review, we will discuss the current understanding of mitochondrial roles in breast cancers and elucidate why mitochondria are a rational therapeutic target. We will then outline the status of the use of mitochondria-targeting drugs in breast cancers, and highlight ClpP agonists as emerging mitochondria-targeting drugs with a unique mechanism of action. We also illustrate possible drug combination strategies and challenges in the future breast cancer clinic.
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影响因子：
3.7
作者：
Alles MC;Gardiner-Garden M;Nott DJ;Wang Y;Foekens JA;Sutherland RL;Musgrove EA;Ormandy CJ
通讯作者：
Ormandy CJ
DOI：
10.1016/j.bbamcr.2011.06.007
发表时间：
2012-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Baker TA;Sauer RT
通讯作者：
Sauer RT
影响因子：
4.6
作者：
Bhandary L;Bailey PC;Chang KT;Underwood KF;Lee CJ;Whipple RA;Jewell CM;Ory E;Thompson KN;Ju JA;Mathias TM;Pratt SJP;Vitolo MI;Martin SS
通讯作者：
Martin SS
影响因子：
12.4
作者：
Campbell KJ;Mason SM;Winder ML;Willemsen RBE;Cloix C;Lawson H;Rooney N;Dhayade S;Sims AH;Blyth K;Tait SWG
通讯作者：
Tait SWG
影响因子：
4.6
作者：
Brodie EJ;Zhan H;Saiyed T;Truscott KN;Dougan DA
通讯作者：
Dougan DA