Protective role of c-Jun NH2-terminal kinase-associated leucine zipper protein (JLP) in curcumin-induced cancer cell death
Protective role of c-Jun NH2-terminal kinase-associated leucine zipper protein (JLP) in curcumin-induced cancer cell death
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DOI：
10.1016/j.bbrc.2019.11.154
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发表时间：
2020-02-12
影响因子：
3.1
通讯作者：
Yoshioka, Katsuji
中科院分区：
文献类型：
--
作者：
Boldbaatar, Jambaldorj;Gunarta, I. Ketut;Yoshioka, Katsuji
以前的研究已经确定了姜黄素的抗肿瘤活性，姜黄素是姜黄的主要成分。越来越多的证据表明，姜黄素诱导自噬，丝裂原活化蛋白激酶（MAPK）的细胞内信号通路的激活，和活性氧（ROS）介导的细胞死亡。c-Jun氨基末端激酶（JNK）相关的亮氨酸拉链蛋白（JLP）是MAPK信号通路的支架蛋白，已被鉴定为癌症的候选生物标志物。在这项研究中，我们探讨了JLP在姜黄素诱导的癌细胞死亡中的作用。我们发现，JLP敲低（KD）增加细胞死亡和细胞内ROS水平。此外，在姜黄素处理的细胞中，JLP KD损害核周区域周围的溶酶体积聚，这导致自噬体-溶酶体融合的抑制，并减弱p38 MAPK活化。细胞活力和p38 MAPK激活的降低通过表达野生型JLP而不是缺乏p38 MAPK结合结构域的JLP突变体来逆转。此外，参与自噬的关键基因的失活增加了对姜黄素诱导的细胞死亡的敏感性。总之，这些结果表明，JLP通过调节溶酶体定位和p38 MAPK信号传导介导自噬的诱导，表明在姜黄素诱导的ROS介导的癌细胞死亡中的总体保护作用。(C)2019爱思唯尔公司All rights reserved.
Previous studies have established the antitumor activity of curcumin, a major component of turmeric. Increasing evidence indicates that curcumin induces autophagy, the activation of mitogen-activated protein kinase (MAPK) intracellular signaling pathways, and reactive oxygen species (ROS)-mediated cell death. The c-Jun NH2-terminal kinase (JNK)-associated leucine zipper protein (JLP), a scaffold protein for MAPK signaling pathways, has been identified as a candidate biomarker for cancer. In this study, we explored the role of JLP in curcumin-induced cancer cell death. We found that JLP knockdown (KD) increases cell death and intracellular ROS levels. Furthermore, JLP KD impaired lysosomal accumulation around perinuclear regions, which led to the inhibition of autophagosome-lysosome fusion, and attenuated p38 MAPK activation in curcumin-treated cells. The decreases in cell viability and p38 MAPK activation were reversed by expressing wild-type JLP but not a JLP mutant lacking the p38 MAPK-binding domain. In addition, the inactivation of a key gene involved in autophagy increased sensitivity to curcumin-induced cell death. Together, these results suggest that JLP mediates the induction of autophagy by regulating lysosome positioning and p38 MAPK signaling, indicating an overall protective role in curcumin-induced ROS-mediated cancer cell death. (C) 2019 Elsevier Inc. All rights reserved.