Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Orthopedic Oncology, Peking University Cancer Hospital& Institute, Beijing, China.
Sci Rep. 2017 Aug 1;7(1):7070. doi: 10.1038/s41598-017-07204-w.
Cisplatin is one of the most efficacious antimitotic drugs used in the treatment of a range of malignant tumors. However, treatment failures are common due to the development of chemoresistance. In addition to its telomere maintenance function, telomerase plays a pro-survival role, inducing decreased apoptosis and increased resistance against DNA damage. Elucidation of the molecular mechanisms underlying this effect is critical to improve treatment outcomes. Previously, our group showed higher telomerase reverse transcriptase(TERT) expression in cisplatin resistant osteosarcoma cells. In this study, confocal fluorescence microscopy experiments revealed that TERT translocates from the nucleus to mitochondria in cisplatin treated osteosarcoma cells. We observed decreased apoptosis rate and improved mitochondrial function in TERT-overexpressing cells following cisplatin treatment. Based on these results, we further established that TERT inhibits cisplatin-induced apoptosis independently of telomerase reverse transcriptase activity. Moreover, TERT suppressed cisplatin-induced apoptosis and improved mitochondrial function via alleviating intracellular ROS in osteosarcoma cells. Our finding that TERT shuttles from the nucleus to the mitochondrion in response to cisplatin treatment and inhibits cisplatin-induced apoptosis in osteosarcoma cells may be especially important to overcome drug resistance.
顺铂是治疗多种恶性肿瘤最有效的抗有丝分裂药物之一。然而，由于化疗耐药的发展，治疗失败很常见。除了其端粒维持功能外，端粒酶还具有促进存活的作用，诱导细胞凋亡减少和对 DNA 损伤的抵抗力增加。阐明这种作用的分子机制对于改善治疗效果至关重要。以前，我们的研究小组表明，在顺铂耐药骨肉瘤细胞中端粒酶逆转录酶（TERT）的表达更高。在这项研究中，共聚焦荧光显微镜实验表明，TERT 在顺铂处理的骨肉瘤细胞中从核转移到线粒体。我们观察到在顺铂处理后，TERT 过表达的细胞凋亡率降低，线粒体功能改善。基于这些结果，我们进一步证实，TERT 独立于端粒酶逆转录酶活性抑制顺铂诱导的细胞凋亡。此外，TERT 通过减轻骨肉瘤细胞中的细胞内 ROS 来抑制顺铂诱导的细胞凋亡和改善线粒体功能。我们发现 TERT 响应顺铂处理从核转移到线粒体，并抑制骨肉瘤细胞中的顺铂诱导的细胞凋亡，这对于克服耐药性可能特别重要。
