Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2high Breast Cancer
Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2high Breast Cancer
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DOI：
10.1089/ars.2016.6677
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发表时间：
2017-01-10
影响因子：
6.6
通讯作者：
Neuzil, Jiri
中科院分区：
文献类型：
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作者：
Rohlenova, Katerina;Sachaphibulkij, Karishma;Neuzil, Jiri
目的：乳腺癌中HER2癌基因的表达与对治疗的抵抗有关，并且HER2可能调节生物能量学。因此，我们研究了电子传递链（ETC）的中断是否是一个可行的策略，以消除Her2（高）diseases.Results：我们表明，Her2（高）细胞和肿瘤增加组装的呼吸超复合物（SC）和增加复杂的I驱动的呼吸在体外和体内。它们对MitoTam也高度敏感，MitoTam是一种新型的他莫昔芬靶向肿瘤的衍生物。与他莫昔芬不同，MitoTam有效抑制实验性Her2（高）肿瘤，而无全身毒性。从机制上讲，MitoTam抑制复合物I驱动的呼吸，并在体外和体内破坏Her2（高）背景下的呼吸SC，导致活性氧产生增加和细胞死亡。有趣的是，Her2（high）细胞对MitoTam的更高敏感性依赖于Her2的线粒体部分。创新：癌基因如HER2可以重组ETC，创造了一个以前未被认识的治疗漏洞，可被SC破坏剂如MitoTam.Conclusion：我们提出ETC是Her2（high）疾病的合适治疗靶点。
Aims: Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2(high) disease.Results: We demonstrate that Her2(high) cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2(high) tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2(high) background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2(high) cells to MitoTam is dependent on the mitochondrial fraction of Her2.Innovation: Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam.Conclusion: We propose that the ETC is a suitable therapeutic target in Her2(high) disease.