Inhibitory Role of TRIP-Br1 Oncoprotein in Anticancer Drug-mediated Programmed Cell Death Via Mitophagy Activation

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2022 Jul 11

PMID 35813469

Authors

Samil Jung

Davaajargal Myagmarjav

Taeyeon Jo

Soonduk Lee

Songyi Han

Nguyen Thi Ngoc Quynh

Nguyen Hai Anh

Son Hai Vu

Yeongseon Choi

Myeong-Sok Lee

Affiliations

Soon will be listed here.

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.

Citing Articles

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Wang M, Liu M, Yang C, Hu Y, Liao X, Liu Q J Cancer. 2024; 15(16):5462-5476.

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