Hu Xiaoqing, Wang Jiabin, Chai Jiannan, Yu Xiaoya, Zhang Yunhan, Feng Yuqi, Qin Jianchun, Yu Huimei
Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, People's Republic of China.
Department of Ophthalmology, First Hospital of Jilin University, Changchun, Jilin 130021, People's Republic of China.
Onco Targets Ther. 2020 Oct 7;13:9967-9976. doi: 10.2147/OTT.S273435. eCollection 2020.
The chemoresistance and toxicity of traditional chemotherapeutic drugs have become obstacles to their antitumor effects in ovarian cancers. Therefore, it is particularly important to develop new anticancer drugs to increase target sensitivity and reduce the toxicity of chemotherapy drugs. As key organelles, the endoplasmic reticulum and mitochondria play important role in chemoresistance. Cells become resistant to drugs by maintaining the homeostasis of the endoplasmic reticulum and mitochondria. Chaetomugilin J, a metabolite isolated from , belongs to the Chaetomium family and exhibits potent cytotoxicity. In this study, we aimed to explore the mechanistic link between apoptosis and endoplasmic reticulum stress, mitophagy and mitochondrial dysfunction induced by chaetomugilin J combined with cisplatin in the ovarian cancer cell line A2780.
Chaetomugilin J was identified by chemical methods. Cell viability was measured by an MTT assay. The apoptosis, mitochondrial membrane potential, and intracellular reactive oxygen species (ROS) were examined by flow cytometry. Mitochondrial ROS was measured by a fluorescence microscope with MitoSox staining. Further, the related proteins and overexpression of parkin were detected by Western blot.
Chaetomugilin J combined with low-dose cisplatin decreased cell viability and increased apoptosis in A2780 cells. In addition, intracellular ROS and mitochondrial ROS were increased, while the mitochondrial membrane potential was reduced. The expressions of grp78 and chop were decreased after treatment by chaetomugilin J combined with low-dose cisplatin. Overexpression of parkin attenuated chaetomugilin J combined with cisplatin-induced apoptosis.
Chaetomugilin J combined with cisplatin inhibited pink1/parkin mediated mitophagy increased mitochondrial dysfunction in the A2780 cells and enhanced apoptosis induced by cisplatin in the ovarian cancer cell line A2780. But this process was not related to endoplasmic reticulum apoptotic pathway.
传统化疗药物的化疗耐药性和毒性已成为其在卵巢癌中发挥抗肿瘤作用的障碍。因此，开发新的抗癌药物以提高靶点敏感性并降低化疗药物的毒性尤为重要。内质网和线粒体作为关键细胞器，在化疗耐药中发挥重要作用。细胞通过维持内质网和线粒体的稳态而对药物产生耐药性。从[具体来源未给出]中分离出的代谢产物Chaetomugilin J属于毛壳菌属，具有强大的细胞毒性。在本研究中，我们旨在探讨Chaetomugilin J联合顺铂在卵巢癌细胞系A2780中诱导的凋亡与内质网应激、线粒体自噬和线粒体功能障碍之间的机制联系。
通过化学方法鉴定Chaetomugilin J。采用MTT法检测细胞活力。通过流式细胞术检测细胞凋亡、线粒体膜电位和细胞内活性氧（ROS）。用MitoSox染色的荧光显微镜检测线粒体ROS。此外，通过蛋白质免疫印迹法检测相关蛋白和帕金蛋白的过表达。
Chaetomugilin J联合低剂量顺铂可降低A2780细胞的活力并增加其凋亡。此外，细胞内ROS和线粒体ROS增加，而线粒体膜电位降低。Chaetomugilin J联合低剂量顺铂处理后，grp78和chop的表达降低。帕金蛋白的过表达减弱了Chaetomugilin J联合顺铂诱导的凋亡。
Chaetomugilin J联合顺铂抑制了pink1/帕金介导的线粒体自噬，增加了A2780细胞中的线粒体功能障碍，并增强了顺铂在卵巢癌细胞系A2780中诱导的凋亡。但这一过程与内质网凋亡途径无关。
