Department of Biology, University of Padua, 35121, Padua, Italy.
Veneto Institute of Molecular Medicine, 35129, Padua, Italy.
Cell Death Dis. 2023 Apr 5;14(4):241. doi: 10.1038/s41419-023-05768-2.
Drug resistance limits the efficacy of chemotherapy and targeted cancer treatments, calling for the identification of druggable targets to overcome it. Here we show that the mitochondria-shaping protein Opa1 participates in resistance against the tyrosine kinase inhibitor gefitinib in a lung adenocarcinoma cell line. Respiratory profiling revealed that oxidative metabolism was increased in this gefitinib-resistant lung cancer cell line. Accordingly, resistant cells depended on mitochondrial ATP generation, and their mitochondria were elongated with narrower cristae. In the resistant cells, levels of Opa1 were increased and its genetic or pharmacological inhibition reverted the mitochondrial morphology changes and sensitized them to gefitinib-induced cytochrome c release and apoptosis. In vivo, the size of gefitinib-resistant lung orthotopic tumors was reduced when gefitinib was combined with the specific Opa1 inhibitor MYLS22. The combo gefitinib-MYLS22 treatment increased tumor apoptosis and reduced its proliferation. Thus, the mitochondrial protein Opa1 participates in gefitinib resistance and can be targeted to overcome it.
耐药性限制了化疗和靶向癌症治疗的疗效，因此需要确定可药物治疗的靶点来克服耐药性。在这里，我们发现线粒体塑形蛋白 Opa1 参与了肺腺癌细胞系对酪氨酸激酶抑制剂吉非替尼的耐药性。呼吸谱分析显示，这种吉非替尼耐药的肺癌细胞系中氧化代谢增加。因此，耐药细胞依赖于线粒体 ATP 的产生，并且它们的线粒体变长，嵴变窄。在耐药细胞中，Opa1 的水平增加，其基因或药理学抑制可逆转线粒体形态的变化，并使它们对吉非替尼诱导的细胞色素 c 释放和细胞凋亡敏感。在体内，当吉非替尼与特定的 Opa1 抑制剂 MYLS22 联合使用时，吉非替尼耐药的肺原位肿瘤的大小减小。吉非替尼-MYLS22 联合治疗增加了肿瘤的凋亡并降低了其增殖。因此，线粒体蛋白 Opa1 参与了吉非替尼耐药性，并可作为靶点来克服它。
