Cystathionine -synthase regulates mitochondrial morphogenesis in ovarian cancer
Cystathionine -synthase regulates mitochondrial morphogenesis in ovarian cancer
复制标题
DOI：
10.1096/fj.201701095r
复制
发表时间：
2018-08-01
期刊：
影响因子：
4.8
通讯作者：
Mukherjee, Priyabrata
中科院分区：
文献类型：
--
作者：
Chakraborty, Prabir Kumar;Murphy, Brennah;Mukherjee, Priyabrata
线粒体形态发生的失调，线粒体融合和裂变过程之间的动态平衡，现在正在演变为一个关键的代谢事件，燃料肿瘤生长和治疗耐药性。然而，支持癌细胞如何重新编程线粒体形态发生的基础知识仍然不完整。在这里，我们报告，胱硫醚合成酶（CBS）重新程序的线粒体形态发生在卵巢癌（OvCa）细胞通过选择性调节稳定的线粒体融合蛋白2（MFN 2）。在临床上，CBS和MFN 2的高表达暗示OvCa患者的总体存活率差，并且CBS和MFN 2表达之间的显著关联存在于同一数据集中的个体患者中。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产生激活JNK的氧化应激。活化的JNK磷酸化MFN 2以募集与E6-AP羧基末端的含有结构域的泛素E3连接酶同源的用于其通过泛素-蛋白酶体系统降解。补充硫化氢或谷胱甘肽（CBS酶活性的催化产物）、抗氧化剂或JNK抑制剂可恢复MFN 2表达。在CBS沉默的原位异种移植肿瘤组织中，MFN 2而不是MFN 1被选择性下调。总之，该报道揭示了OvCa中线粒体形态发生失调的作用，提出了这种失调的机制之一，并提供了通过调节代谢酶CBS来纠正它的方法。Murphy，B.，马斯特尔，S. B.，戴，A.，Xiong，X.，Rao，G.，纳兹，S.，张，M.，杨，D.，Dhanasekaran，D. N.，巴塔查里亚河，巴西-地Mukherjee，P.胱硫醚合酶调节卵巢癌的线粒体形态发生。
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 -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 -synthase regulates mitochondrial morphogenesis in ovarian cancer.