Mitochondrial ROS Produced in Human Colon Carcinoma Associated with Cell Survival via Autophagy.

Abstract

Simple SummaryHuman colon carcinoma remains one of the major causes of cancer-related death worldwide. Ubiquinol cytochrome c reductase binding protein (UQCRB) has been reported as a biomarker of colorectal cancer, but its role in tumor growth has not been clarified. CRC cells often exhibit high autophagic flux under nutrient deprivation or hypoxic condition and increased autophagy activation in cancer cells involving the recycling of cell components to facilitate survival in a tumor microenvironment. Here we show that UQCRB is overexpressed in HCT116 cells compared to CCD18co, normal colon fibroblast cells. Mechanistically, the increasing level of mitochondrial ROS (mROS) caused by UQCRB overexpression can release Ca2+ by the activation of the lysosomal transient receptor potential mucolipin 1 channels. This activation triggers transcription factor EB nuclear translocation and lysosome biogenesis leading to autophagy flux. Collectively, we identified that the increasing level of mROS by the overexpression of UQCRB in human colon carcinoma could link to autophagy for colorectal cancer survival. These results lead to a translational impact that a UQCRB inhibitor could be a potential anticancer agent for human colon carcinoma treatment.Human colon carcinomas, including HCT116 cells, often exhibit high autophagic flux under nutrient deprivation or hypoxic conditions. Mitochondrial ROS (mROS) is known as a ‘molecular switch’ for regulating the autophagic pathway, which is critical for directing cancer cell survival or death. In early tumorigenesis, autophagy plays important roles in maintaining cellular homeostasis and contributes to tumor growth. However, the relationships between mROS and the autophagic capacities of HCT116 cells are poorly understood. Ubiquinol cytochrome c reductase binding protein (UQCRB) has been reported as a biomarker of colorectal cancer, but its role in tumor growth has not been clarified. Here, we showed that UQCRB is overexpressed in HCT116 cells compared to CCD18co cells, a normal colon fibroblast cell line. Pharmacological inhibition of UQCRB reduced mROS levels, autophagic flux, and the growth of HCT116 tumors in a xenograft mouse model. We further investigated mutant UQCRB-overexpressing cell lines to identify functional links in UQCRB-mROS-autophagy. Notably, an increasing level of mROS caused by UQCRB overexpression released Ca2+ by the activation of lysosomal transient receptor potential mucolipin 1 (TRPML1) channels. This activation induced transcription factor EB (TFEB) nuclear translocation and lysosome biogenesis, leading to autophagy flux. Collectively, our study showed that increasing levels of mROS caused by the overexpression of UQCRB in human colon carcinoma HCT116 cells could be linked to autophagy for cell survival.