Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
FASEB J. 2018 Aug;32(8):4145-4157. doi: 10.1096/fj.201701095R. Epub 2018 Mar 1.
Deregulation of mitochondrial morphogenesis, a dynamic equilibrium between mitochondrial fusion and fission processes, is now evolving as a key metabolic event that fuels tumor growth and therapy resistance. However, fundamental knowledge underpinning how cancer cells reprogram mitochondrial morphogenesis remains incomplete. Here, we report that cystathionine β-synthase (CBS) reprograms mitochondrial morphogenesis in ovarian cancer (OvCa) cells by selectively regulating the stability of mitofusin 2 (MFN2). Clinically, high expression of both CBS and MFN2 implicates poor overall survival of OvCa patients, and a significant association between CBS and MFN2 expression exists in individual patients in the same data set. The silencing of CBS by small interfering RNA or inhibition of its catalytic activity by a small molecule inhibitor creates oxidative stress that activates JNK. Activated JNK phosphorylates MFN2 to recruit homologous to the E6-AP carboxyl terminus' domain-containing ubiquitin E3 ligase for its degradation via the ubiquitin-proteasome system. Supplementation with hydrogen sulfide or glutathione (the catalytic products of CBS enzymatic activity), anti-oxidants, or a JNK inhibitor restores MFN2 expression. In CBS-silenced orthotopic xenograft tumor tissues, MFN2 but not MFN1 is selectively downregulated. In summary, this report reveals a role for deregulated mitochondrial morphogenesis in OvCa, suggests one of the mechanisms for this deregulation, and provides a way to correct it through modulation of the metabolic enzyme CBS.-Chakraborty, P. K., Murphy, B., Mustafi, S. B., Dey, A., Xiong, X., Rao, G., Naz, S., Zhang, M., Yang, D., Dhanasekaran, D. N., Bhattacharya, R., Mukherjee, P. Cystathionine β-synthase regulates mitochondrial morphogenesis in ovarian cancer.
线粒体形态发生的去调控，即线粒体融合和裂变过程之间的动态平衡，现在正成为推动肿瘤生长和治疗抵抗的关键代谢事件。然而，癌症细胞重新编程线粒体形态发生的基本知识仍然不完整。在这里，我们报告胱硫醚β合酶（CBS）通过选择性调节融合蛋白 2（MFN2）的稳定性来重新编程卵巢癌细胞的线粒体形态发生。临床上，CBS 和 MFN2 的高表达暗示卵巢癌患者的总生存率较差，并且在同一数据集中的个别患者中存在 CBS 和 MFN2 表达之间的显著关联。通过小干扰 RNA 沉默 CBS 或通过小分子抑制剂抑制其催化活性会产生氧化应激，从而激活 JNK。激活的 JNK 磷酸化 MFN2，募集同源物到 E6-AP 羧基末端结构域包含的泛素 E3 连接酶，通过泛素-蛋白酶体系统进行降解。用硫化氢或谷胱甘肽（CBS 酶活性的催化产物）、抗氧化剂或 JNK 抑制剂进行补充可以恢复 MFN2 的表达。在 CBS 沉默的原位异种移植肿瘤组织中，MFN2 而不是 MFN1 被选择性地下调。总之，本报告揭示了失调的线粒体形态发生在卵巢癌中的作用，提出了这种失调的一种机制，并通过调节代谢酶 CBS 提供了一种纠正它的方法。-Chakraborty, P. K., Murphy, B., Mustafi, S. B., Dey, A., Xiong, X., Rao, G., Naz, S., Zhang, M., Yang, D., Dhanasekaran, D. N., Bhattacharya, R., Mukherjee, P. Cystathionine β-synthase regulates mitochondrial morphogenesis in ovarian cancer.
