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TRIP-Br1 癌蛋白通过激活线粒体自噬在抗癌药物介导的程序性细胞死亡中发挥抑制作用。

Inhibitory role of TRIP-Br1 oncoprotein in anticancer drug-mediated programmed cell death via mitophagy activation.

机构信息

Division of Biological Sciences, Sookmyung Women's University, Seoul, 14310, South Korea.

出版信息

Int J Biol Sci. 2022 May 29;18(9):3859-3873. doi: 10.7150/ijbs.72138. eCollection 2022.

DOI:10.7150/ijbs.72138
PMID:35813469
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9254482/
Abstract

Chemotherapy has been widely used as a clinical treatment for cancer over the years. However, its effectiveness is limited because of resistance of cancer cells to programmed cell death (PCD) after treatment with anticancer drugs. To elucidate the resistance mechanism, we initially focused on cancer cell-specific mitophagy, an autophagic degradation of damaged mitochondria. This is because mitophagy has been reported to provide cancer cells with high resistance to anticancer drugs. Our data showed that TRIP-Br1 oncoprotein level was greatly increased in the mitochondria of breast cancer cells after treatment with various anticancer drugs including staurosporine (STS), the main focus of this study. STS treatment increased cellular ROS generation in cancer cells, which triggered mitochondrial translocation of TRIP-Br1 from the cytosol via dephosphorylation of TRIP-Br1 by protein phosphatase 2A (PP2A). Up-regulated mitochondrial TRIP-Br1 suppressed cellular ROS levels. In addition, TRIP-Br1 rapidly removed STS-mediated damaged mitochondria by activating mitophagy. It eventually suppressed STS-mediated PCD via degradation of VDACI, TOMM20, and TIMM23 mitochondrial membrane proteins. TRIP-Br1 enhanced mitophagy by increasing expression levels of two crucial lysosomal proteases, cathepsins B and D. In conclusion, TRIP-Br1 can suppress the sensitivity of breast cancer cells to anticancer drugs by activating autophagy/mitophagy, eventually promoting cancer cell survival.

摘要

多年来，化疗已被广泛用作癌症的临床治疗方法。然而，由于癌细胞在接受抗癌药物治疗后对程序性细胞死亡（PCD）的抵抗，其疗效有限。为了阐明耐药机制，我们最初专注于癌细胞特异性的线粒体自噬，即受损线粒体的自噬降解。这是因为已经报道线粒体自噬为癌细胞提供了对抗癌药物的高度耐药性。我们的数据显示，在各种抗癌药物（包括 staurosporine（STS））处理后，乳腺癌细胞的线粒体中 TRIP-Br1 癌蛋白水平大大增加，STS 是本研究的主要焦点。STS 处理增加了癌细胞中的细胞 ROS 生成，这通过蛋白磷酸酶 2A（PP2A）使 TRIP-Br1 去磷酸化，触发 TRIP-Br1 从细胞质向线粒体易位。上调的线粒体 TRIP-Br1 抑制细胞 ROS 水平。此外，TRIP-Br1 通过激活线粒体自噬快速去除 STS 介导的受损线粒体。它最终通过降解 VDACI、TOMM20 和 TIMM23 线粒体膜蛋白来抑制 STS 介导的 PCD。TRIP-Br1 通过增加两种关键溶酶体蛋白酶，组织蛋白酶 B 和 D 的表达水平来增强线粒体自噬。总之，TRIP-Br1 通过激活自噬/线粒体自噬来抑制乳腺癌细胞对抗癌药物的敏感性，最终促进癌细胞存活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89a0/9254482/b0b1929139be/ijbsv18p3859g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89a0/9254482/b0e3deadbd6e/ijbsv18p3859g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89a0/9254482/b0b1929139be/ijbsv18p3859g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89a0/9254482/b0e3deadbd6e/ijbsv18p3859g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89a0/9254482/cd95c7762d47/ijbsv18p3859g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89a0/9254482/954552a94673/ijbsv18p3859g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89a0/9254482/4e8b56bd67cc/ijbsv18p3859g004.jpg
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