Kong Bao, Tsuyoshi Hideaki, Orisaka Makoto, Shieh Dar-Bin, Yoshida Yoshio, Tsang Benjamin K
Department of Obstetrics and Gynecology, Department of Cellular and Molecular Medicine, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada.
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Ann N Y Acad Sci. 2015 Sep;1350:1-16. doi: 10.1111/nyas.12883.
Chemoresistance enables cancer cells to evade apoptotic stimuli and leads to poor clinical prognosis. It arises from dysregulation of signaling factors responsible for inducing cell proliferation and death and for modulating the microenvironment. In gynecologic cancers, p53 is a pivotal determinant of cisplatin sensitivity, while BCL-2 family members are associated with taxane sensitivity. Mitochondria fusion and fission dynamics are required for many mitochondrial functions and are also involved in mitochondria-mediated apoptosis, which is closely associated with chemosensitivity. Mitochondrial dynamics are controlled by a number of intracellular proteins, including fusion (Opa1 and mitofusion 1 and 2) and fission proteins (Drp1 and Fis1), which can be proapoptotic or antiapoptotic, depending on the cell types, status, and stimuli from the microenvironment. This paper describes the role of mitochondrial dynamics in the mechanism of chemoresistance and the evidence supporting a significant contribution of a hyperfusion state to chemoresistance in gynecological cancers. Moreover, we discuss our findings showing that enforced fission induces apoptosis of cancer cells and sensitizes them to chemotherapeutic agents. Understanding the regulation of mitochondrial dynamics in chemoresistance may provide insight into new biomarkers that better predict cancer chemosensitivity and may aid the development of effective therapeutic strategies for clinical management of gynecologic cancers.
化疗耐药使癌细胞能够逃避凋亡刺激，导致临床预后不良。它源于负责诱导细胞增殖和死亡以及调节微环境的信号因子失调。在妇科癌症中，p53是顺铂敏感性的关键决定因素，而BCL-2家族成员与紫杉烷敏感性相关。线粒体融合和裂变动力学是许多线粒体功能所必需的，也参与线粒体介导的凋亡，这与化疗敏感性密切相关。线粒体动力学受多种细胞内蛋白质控制，包括融合蛋白（Opa1和线粒体融合蛋白1和2）和裂变蛋白（Drp1和Fis1），根据细胞类型、状态和微环境刺激，它们可以是促凋亡的或抗凋亡的。本文描述了线粒体动力学在化疗耐药机制中的作用，以及支持高融合状态对妇科癌症化疗耐药有重大贡献的证据。此外，我们讨论了我们的研究结果，即强制裂变诱导癌细胞凋亡并使其对化疗药物敏感。了解化疗耐药中线粒体动力学的调节可能有助于深入了解更好预测癌症化疗敏感性的新生物标志物，并可能有助于开发用于妇科癌症临床管理的有效治疗策略。
