HINT2 triggers mitochondrial Ca2+ influx by regulating the mitochondrial Ca2+ uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer
HINT2 triggers mitochondrial Ca2+ influx by regulating the mitochondrial Ca2+ uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer
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DOI：
10.1016/j.canlet.2017.09.020
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发表时间：
2017-12-28
期刊：
影响因子：
9.7
通讯作者：
Wang, Weilin
中科院分区：
文献类型：
--
作者：
Chen, Linghui;Sun, Qiang;Wang, Weilin
在早期研究中，显示使细胞对线粒体凋亡敏感的HINT 2在肝细胞癌（HCC）细胞中下调（Martin et al.，2006年）。然而，这种效应的分子机制尚不清楚。免疫组化显示HINT 2在胰腺癌组织中的表达较癌旁组织低（P < 0.05）。此外，其表达与病理分级和淋巴结转移有关（P = 0.0161和0.0108，分别）;此外，HINT 2的下调被发现与胰腺癌患者的预后相对较差。HINT 2的上调显示出触发胰腺癌细胞凋亡，降低线粒体膜电位（三角形psi（m）），促进细胞内活性氧（ROS）产生，并升高线粒体Ca 2+水平。然而，与钌红共同处理HINT 2过表达的BxPC-3细胞部分抑制HINT 2诱导的细胞凋亡，这与三角psi（m）的减少以及细胞内ROS和线粒体Ca 2+的增加有关。根据我们的研究结果，“在用Adv-HINT 2转导的细胞中，线粒体钙摄取1和2（MICU 1和MICU 2）被下调，基本MCU调节器（EMRE）被上调。因此，我们推断HINT 2通过线粒体钙单向转运体（MCU）调节线粒体Ca 2+内流来触发胰腺癌细胞的凋亡。此外，我们发现HINT 2可以使BxPC-3和L3.6pl细胞对吉西他滨诱导的凋亡敏感，并且吉西他滨上调HINT 2表达。这表明吉西他滨诱导的细胞凋亡与HINT 2水平有关。(c)2017作者由爱思唯尔公司出版
In early studies, it was shown that HINT2, which sensitizes cells to mitochondrial apoptosis, is downregulated in hepatocellular carcinoma (HCC) cells (Martin et al., 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 (triangle psi(m)), 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 triangle psi(m) 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. (c) 2017 The Authors. Published by Elsevier B.V.