NOX2-Mediated TFEB Activation and Vacuolization Regulate Lysosome-Associated Cell Death Induced by Gypenoside L, a Saponin Isolated from Gynostemma pentaphyllum.
NOX2-Mediated TFEB Activation and Vacuolization Regulate Lysosome-Associated Cell Death Induced by Gypenoside L, a Saponin Isolated from Gynostemma pentaphyllum.
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NOX2 介导的 TFEB 激活和空泡化调节绞股蓝皂苷 L（一种从绞股蓝中分离出的皂苷）诱导的溶酶体相关细胞死亡。
DOI：
10.1021/acs.jafc.7b02296
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发表时间：
2017-07
影响因子：
6.1
通讯作者：
He Zhendan
中科院分区：
文献类型：
--
作者：
Zheng Kai;Jiang Yingchun;Liao Chenghui;Hu Xiaopeng;Li Yan;Zeng Yong;Zhang Jian;Wu Xuli;Wu Haiqiang;Liu Lizhong;Wang Yifei;He Zhendan
凋亡信号通路的下调和保护性自噬的激活是肿瘤细胞耐药的主要机制。因此，迫切需要探索有效的化疗药物或分离新的天然产物，以触发非凋亡和非自噬细胞死亡，如溶酶体相关死亡。我们最近从绞股蓝中提取了一种皂苷，绞股蓝皂苷L (gypp -L)，并表明gypp -L能够诱导与溶酶体肿胀相关的食管癌细胞的非凋亡细胞死亡。然而，空泡化和溶酶体在细胞死亡中的作用尚不清楚。在此，我们揭示了NADPH氧化酶nox2介导的空泡化和转录因子EB （TFEB）激活在溶酶体相关细胞死亡中的关键作用。我们发现，gypl最初诱导异常增大和碱化的液泡，这是由脂筏依赖的内吞作用产生的。此外，NOX2被激活以促进空泡化和不依赖mtorc1的tfeb介导的溶酶体生物发生。最后，提高溶酶体的pH值可以促进gypl诱导的细胞死亡。这些发现提示nox2 - tfeb介导的溶酶体生物发生在癌症耐药中的保护作用以及脂筏和空泡化之间的紧密相互作用。此外，通过诱导溶酶体相关细胞死亡，可以利用gypp - l作为克服耐药的替代选择。
Downregulation of apoptotic signal pathway and activation of protective autophagy mainly contribute to the chemoresistance of tumor cells. Therefore, exploring efficient chemotherapeutic agents or isolating novel natural products that can trigger nonapoptotic and nonautophagic cell death such as lysosome-associated death is emergently required. We have recently extracted a saponin, gypenoside L (Gyp-L), from Gynostemma pentaphyllum and showed that Gyp-L was able to induce nonapoptotic cell death of esophageal cancer cells associated with lysosome swelling. However, contributions of vacuolization and lysosome to cell death remain unclear. Herein, we reveal a critical role for NADPH oxidase NOX2-mediated vacuolization and transcription factor EB (TFEB) activation in lysosome-associated cell death. We found that Gyp-L initially induced the abnormal enlarged and alkalized vacuoles, which were derived from lipid rafts dependent endocytosis. Besides, NOX2 was activated to promote vacuolization and mTORC1-independent TFEB-mediated lysosome biogenesis. Finally, raising lysosome pH could enhance Gyp-L induced cell death. These findings suggest a protective role of NOX2-TFEB-mediated lysosome biogenesis in cancer drug resistance and the tight interaction between lipid rafts and vacuolization. In addition, Gyp-L can be utilized as an alternative option to overcome drug-resistance though inducing lysosome associated cell death.
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影响因子：
28.5
作者：
Yoshida GJ
通讯作者：
Yoshida GJ
影响因子：
21.3
作者：
Medina DL;Di Paola S;Peluso I;Armani A;De Stefani D;Venditti R;Montefusco S;Scotto-Rosato A;Prezioso C;Forrester A;Settembre C;Wang W;Gao Q;Xu H;Sandri M;Rizzuto R;De Matteis MA;Ballabio A
通讯作者：
Ballabio A
DOI：
10.1083/jcb.201003086
发表时间：
2010-11-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hayer A;Stoeber M;Ritz D;Engel S;Meyer HH;Helenius A
通讯作者：
Helenius A
影响因子：
9.2
作者：
Bosch, Marta;Mari, Montserrat;Herms, Albert;Fernandez, Ana;Fajardo, Alba;Kassan, Adam;Giralt, Albert;Colell, Anna;Balgoma, David;Barbero, Elisabet;Gonzalez-Moreno, Elena;Matias, Nuria;Tebar, Francesc;Balsinde, Jesus;Camps, Marta;Enrich, Carlos;Gross, Steven P.;Garcia-Ruiz, Carmen;Perez-Navarro, Esther;Fernandez-Checa, Jose C.;Pol, Albert
通讯作者：
Pol, Albert
DOI：
10.1038/nrm3565
发表时间：
2013-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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