Abstract：
Tamoxifen (TAM) resistance presents a major clinical obstacle in the management of estrogen-sensitive breast cancer, highlighting the need to understand the underlying mechanisms and potential therapeutic approaches. We showed that dysregulated mitochondrial dynamics were involved in TAM resistance by protecting against mitochondrial apoptosis. The dysregulated mitochondrial dynamics were associated with increased mitochondrial fusion and decreased fission, thus preventing the release of mitochondrial cytochrome c to the cytoplasm following TAM treatment. Dynamin-related GTPase protein mitofusin 1 (MFN1), which promotes fusion, was upregulated in TAM-resistant cells, and high MFN1 expression indicated a poor prognosis in TAM-treated patients. Mitochondrial translocation of MFN1 and interaction between MFN1 and mitofusin 2 (MFN2) were enhanced to promote mitochondrial outer membrane fusion. The interaction of MFN1 and cristae-shaping protein optic atrophy 1 (OPA1) and OPA1 oligomerization were reduced due to augmented OPA1 proteolytic cleavage, and their apoptosis-promoting function was reduced due to cristae remodeling. Furthermore, the interaction of MFN1 and BAK were increased, which restrained BAK activation following TAM treatment. Knockdown or pharmacological inhibition of MFN1 blocked mitochondrial fusion, restored BAK oligomerization and cytochrome c release, and amplified activation of caspase-3/9, thus sensitizing resistant cells to apoptosis and facilitating the therapeutic effects of TAM both in vivo and in vitro. Conversely, overexpression of MFN1 alleviated TAM-induced mitochondrial apoptosis and promoted TAM resistance in sensitive cells. These results revealed that dysregulated mitochondrial dynamics contributes to the development of TAM resistance, suggesting that targeting MFN1-mediated mitochondrial fusion is a promising strategy to circumvent TAM resistance.
摘要：
他莫昔芬（TAM）耐药是治疗雌激素敏感型乳腺癌的主要临床障碍，强调需要了解潜在的机制和潜在的治疗方法。我们表明，线粒体动力学失调通过保护线粒体凋亡参与TAM抵抗。线粒体动力学失调与线粒体融合增加和裂变减少有关，从而防止TAM处理后线粒体细胞色素c释放到细胞质中。动力蛋白相关GTP酶蛋白线粒体蛋白1（MFN1），促进融合，在TAM抗性细胞中上调，MFN1高表达提示TAM治疗患者预后不良。MFN1的线粒体易位和MFN1与线粒体蛋白2（MFN2）之间的相互作用被增强以促进线粒体外膜融合。由于OPA1蛋白水解裂解增强，MFN1和cr形蛋白视神经萎缩1（OPA1）和OPA1寡聚化的相互作用减少，并且它们的促凋亡功能由于cr重塑而降低。此外，MFN1和BAK的相互作用增加，抑制了TAM治疗后的BAK激活。敲除或药物抑制MFN1阻断的线粒体融合，恢复BAK寡聚化和细胞色素c释放，并扩增caspase-3/9的激活，从而使抗性细胞对凋亡敏感，并促进TAM在体内和体外的治疗作用。相反，MFN1的过表达减轻了TAM诱导的敏感细胞线粒体凋亡并促进了TAM抵抗。这些结果表明，线粒体动力学失调有助于TAM抗性的发展，提示靶向MFN1介导的线粒体融合是规避TAM耐药的有前景的策略。
