(-)-Epigallocatechin-3-gallate induces non-apoptotic cell death in human cancer cells via ROS-mediated lysosomal membrane permeabilization.
(-)-Epigallocatechin-3-gallate induces non-apoptotic cell death in human cancer cells via ROS-mediated lysosomal membrane permeabilization.
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DOI：
10.1371/journal.pone.0046749
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shen HM
中科院分区：
文献类型：
--
作者：
Zhang Y;Yang ND;Zhou F;Shen T;Duan T;Zhou J;Shi Y;Zhu XQ;Shen HM
表没食子儿茶素没食子酸酯(−)是目前研究最广泛的具有抗癌功能的茶多酚。在这项研究中，我们报告了一种新的作用机制，通过确定溶酶体膜通透性(LMP)在EGCG介导的细胞死亡中的关键作用。首先，EGCG诱导的人癌细胞(包括HepG2和HeLa)的细胞死亡不依赖于caspase，并伴随着明显的胞浆空泡化，只有在无血清培养条件下才能观察到。在EGCG处理的细胞中观察到的胞浆空泡化很可能是由溶酶体扩张引起的。有趣的是，EGCG能够通过破坏溶酶体功能来破坏降解阶段的自噬通量，并且EGCG诱导的细胞死亡不依赖于ATG5或自噬。这项研究的关键发现是EGCG能够触发LMP，如Lyso-Tracker Red染色、组织蛋白酶D胞浆易位和胞浆酸化。一直以来，溶酶体促进剂氯喹通过抑制LMP引起的胞浆酸化有效地挽救了细胞死亡。最后，我们发现EGCG促进LMP上游细胞内ROS的产生和细胞死亡，这从EGCG处理的细胞中ROS水平的增加和抗氧化剂N-乙酰半胱氨酸(NAC)对EGCG介导的LMP和细胞死亡的保护作用中得到了证明。综上所述，我们研究的数据揭示了EGCG诱导细胞死亡的一种新机制，涉及ROS和LMP。因此，了解这一溶酶体相关的细胞死亡途径有助于了解EGCG的抗癌作用。
(−)-Epigallocatechin-3-gallate (EGCG) is the most extensive studied tea polyphenol for its anti-cancer function. In this study, we report a novel mechanism of action for EGCG-mediated cell death by identifying the critical role of lysosomal membrane permeabilization (LMP). First, EGCG-induced cell death in human cancer cells (both HepG2 and HeLa) was found to be caspase-independent and accompanied by evident cytosolic vacuolization, only observable when cells were treated in serum-free medium. The cytosolic vacuolization observed in EGCG-treated cells was most probably caused by lysosomal dilation. Interestingly, EGCG was able to disrupt autophagic flux at the degradation stage by impairment of lysosomal function, and EGCG-induced cell death was independent of Atg5 or autophagy. The key finding of this study is that EGCG is able to trigger LMP, as evidenced by Lyso-Tracker Red staining, cathepsin D cytosolic translocation and cytosolic acidification. Consistently, a lysosomotropic agent, chloroquine, effectively rescues the cell death via suppressing LMP-caused cytosolic acidification. Lastly, we found that EGCG promotes production of intracellular ROS upstream of LMP and cell death, as evidenced by increased level of ROS in cells treated with EGCG and the protective effects of antioxidant N-acetylcysteine (NAC) against EGCG-mediated LMP and cell death. Taken together, data from our study reveal a novel mechanism underlying EGCG-induced cell death involving ROS and LMP. Therefore, understanding this lysosome-associated cell death pathway shed new lights on the anti-cancer effects of EGCG.
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影响因子：
3.9
作者：
Lambert JD;Elias RJ
通讯作者：
Elias RJ
影响因子：
4.8
作者：
Liu, D;Martino, G;Srikant, CB
通讯作者：
Srikant, CB
影响因子：
4.8
作者：
Elbling, L;Weiss, RM;Mickshe, M
通讯作者：
Mickshe, M
DOI：
10.1073/pnas.1118193109
发表时间：
2012-05-22
影响因子：
11.1
作者：
McAfee, Quentin;Zhang, Zhihui;Amaravadi, Ravi K.
通讯作者：
Amaravadi, Ravi K.
DOI：
10.1006/bbrc.2001.5293
发表时间：
2001-08-03
影响因子：
3.1
作者：
Hayakawa, S;Saeki, K;Isemura, M
通讯作者：
Isemura, M