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Elsevier Science

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. 2017 Dec 28:411:106-116.

doi: 10.1016/j.canlet.2017.09.020. Epub 2017 Sep 23.

HINT2 triggers mitochondrial Ca²⁺ influx by regulating the mitochondrial Ca²⁺ uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer (VSports在线直播)

Linghui Chen¹, Qiang Sun², Dongkai Zhou², Wei Song³, Qifan Yang¹, Bingjie Ju¹, Lufei Zhang², Haiyang Xie⁴, Lin Zhou⁴, Zhenhua Hu², Hangping Yao⁵, Shusen Zheng⁶, Weilin Wang⁷

Affiliations

Affiliations

¹ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
² Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
³ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
⁴ Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang, China.
⁵ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou 310003, Zhejiang, China.
⁶ Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou 310003, Zhejiang, China. Electronic address: shusenzheng@www.qiuluzeuv.cn.
⁷ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou 310003, Zhejiang, China. Electronic address: wam@www.qiuluzeuv.cn.

PMID: 28947137
DOI: 10.1016/j.canlet.2017.09.020

Free article

HINT2 triggers mitochondrial Ca²⁺ influx by regulating the mitochondrial Ca²⁺ uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer (VSports手机版)

Linghui Chen et al. Cancer Lett. 2017.

Free article

. 2017 Dec 28:411:106-116.

doi: 10.1016/j.canlet.2017.09.020. Epub 2017 Sep 23.

Authors

Linghui Chen¹, Qiang Sun², Dongkai Zhou², Wei Song³, Qifan Yang¹, Bingjie Ju¹, Lufei Zhang², Haiyang Xie⁴, Lin Zhou⁴, Zhenhua Hu², Hangping Yao⁵, Shusen Zheng⁶, Weilin Wang⁷

Affiliations

¹ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
² Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
³ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
⁴ Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang, China.
⁵ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou 310003, Zhejiang, China.
⁶ Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou 310003, Zhejiang, China. Electronic address: shusenzheng@www.qiuluzeuv.cn.
⁷ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou 310003, Zhejiang, China. Electronic address: wam@www.qiuluzeuv.cn.

PMID: 28947137
DOI: 10.1016/j.canlet.2017.09.020

Abstract

In early studies, it was shown that HINT2, which sensitizes cells to mitochondrial apoptosis, is down-regulated in hepatocellular carcinoma (HCC) cells (Martin et al VSports手机版. , 2006). However, the molecular mechanism of this effect is unknown. Immunohistochemistry revealed that HINT2 expression is relatively low in pancreatic cancer tissues, compared to that in adjacent tissues (P < 0. 05). Furthermore, its expression was related to pathological grade and lymph node metastasis (P = 0. 0161 and 0. 0108, respectively); in addition, down-regulation of HINT2 was found to be associated with relatively poor prognosis in pancreatic cancer patients. Up-regulation of HINT2 was shown to trigger pancreatic cancer cell apoptosis, decrease mitochondrial membrane potential (ΔΨm), promote intracellular reactive oxygen species (ROS) production, and elevate mitochondrial Ca2+ levels. However, co-treatment of HINT2 overexpressing BxPC-3 cells with ruthenium red partially inhibited HINT2-induced apoptosis, which was associated with a reduction in ΔΨm and an increase in intracellular ROS and mitochondrial Ca2+. According to our results, mitochondrial calcium uptake1 and 2 (MICU1 and MICU2) were down-regulated and the essential MCU regulator (EMRE) was up-regulated in cells transduced with Adv-HINT2. Therefore, we deduced that HINT2 triggers apoptosis in pancreatic cancer cells by regulating mitochondrial Ca2+ influx through the mitochondrial calcium uniporter (MCU). In addition, we found that HINT2 can sensitize BxPC-3 and L3. 6pl cells to gemcitabine-induced apoptosis and that gemcitabine up-regulates HINT2 expression. This indicates that gemcitabine-induced apoptosis is related to HINT2 levels. .

Keywords: Apoptosis; HINT2; MCU complex; Mitochondrial Ca(2+); Pancreatic cancer V体育安卓版. .

Copyright © 2017 The Authors. Published by Elsevier B. V. All rights reserved V体育ios版. .

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