Tingting Ren1, Jiaojiao Wang1, Hui Zhang2, Peng Yuan2, Jianjun Zhu1, Yousheng Wu1, Qichao Huang1, Xu Guo1, Jing Zhang1, Lele Ji1, Jibin Li1, Hongxin Zhang2, Hushan Yang3, Jinliang Xing1. 1. 1 State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an, China . 2. 2 Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University , Xi'an, China . 3. 3 Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University , Philadelphia, Pennsylvania.
Abstract
AIMS: Levels of the mitochondrial calcium uniporter regulator 1 (MCUR1) increases during development of hepatocellular carcinoma (HCC). However, mechanisms of how mitochondrial Ca2+ homeostasis is modulated and its function remain limited in cancers. RESULTS: MCUR1 was frequently upregulated in HCC cells to enhance the Ca2+ uptake into mitochondria in an MCU-dependent manner, which significantly facilitated cell survival by inhibiting mitochondria-dependent intrinsic apoptosis and promoting proliferation of HCC cells, and thus led to poor prognosis. In vivo assay confirmed these results, indicating that overexpressed MCUR1 notably decreased the fraction of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and increased the positive Ki67 staining in xenograft tumors, while reduced MCUR1 expression was associated with impaired growth capacity of HCC cells in nude mice. The survival advantage conferred by MCUR1-mediated mitochondrial Ca2+ uptake was majorly caused by elevated production of mitochondrial reactive oxygen species and subsequent AKT/MDM2- induced P53 degradation, which regulated the expression level of apoptosis-related molecules and cell cycle-related molecules. Treatment of mitochondrial Ca2+-buffering protein parvalbumin remarkably inhibited the growth of HCC cells. Conclusions and Innovation: Our study provides evidence supporting a possible tumor-promoting role for MCUR1-mediated mitochondrial Ca2+ uptake and uncovers a mechanistic understanding that links change of mitochondrial Ca2+ homeostasis to cancer cell survival, which suggests a potential novel therapeutic target for HCC. Antioxid. Redox Signal. 28, 1120-1136.
AIMS: Levels of the mitochondrial calcium uniporter regulator 1 (MCUR1) increases during development of hepatocellular carcinoma (HCC). However, mechanisms of how mitochondrial Ca2+ homeostasis is modulated and its function remain limited in cancers. RESULTS:MCUR1 was frequently upregulated in HCC cells to enhance the Ca2+ uptake into mitochondria in an MCU-dependent manner, which significantly facilitated cell survival by inhibiting mitochondria-dependent intrinsic apoptosis and promoting proliferation of HCC cells, and thus led to poor prognosis. In vivo assay confirmed these results, indicating that overexpressed MCUR1 notably decreased the fraction of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and increased the positive Ki67 staining in xenograft tumors, while reduced MCUR1 expression was associated with impaired growth capacity of HCC cells in nude mice. The survival advantage conferred by MCUR1-mediated mitochondrial Ca2+ uptake was majorly caused by elevated production of mitochondrial reactive oxygen species and subsequent AKT/MDM2- induced P53 degradation, which regulated the expression level of apoptosis-related molecules and cell cycle-related molecules. Treatment of mitochondrial Ca2+-buffering protein parvalbumin remarkably inhibited the growth of HCC cells. Conclusions and Innovation: Our study provides evidence supporting a possible tumor-promoting role for MCUR1-mediated mitochondrial Ca2+ uptake and uncovers a mechanistic understanding that links change of mitochondrial Ca2+ homeostasis to cancer cell survival, which suggests a potential novel therapeutic target for HCC. Antioxid. Redox Signal. 28, 1120-1136.