JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

Accepted manuscript available online (unedited version)

AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer

Author(s): Yi LI, Wenyan SHE, Xiaoran XU, Yixin LIU, Xinyu WANG, Sheng TIAN, Shiyi LI, Miao WANG, Chaochao YU, Pan LIU, Tianhe HUANG, Yongchang WEI
Affiliation(s): Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China; more
Corresponding email(s): weiyongchang@whu.edu.cn, zn004593@whu.edu.cn
Key Words: N-‍(4-‍(1, 3, 2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2); Gastric cancer; Reactive oxygen species (ROS); Apoptosis; Pyruvate dehydrogenase kinase 1 (PDK1); Glucose metabolism

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Yi LI, Wenyan SHE, Xiaoran XU, Yixin LIU, Xinyu WANG, Sheng TIAN, Shiyi LI, Miao WANG, Chaochao YU, Pan LIU, Tianhe HUANG, Yongchang WEI. AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200351

@article{title="AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer",
author="Yi LI, Wenyan SHE, Xiaoran XU, Yixin LIU, Xinyu WANG, Sheng TIAN, Shiyi LI, Miao WANG, Chaochao YU, Pan LIU, Tianhe HUANG, Yongchang WEI",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2200351"
}

%0 Journal Article
%T AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer
%A Yi LI
%A Wenyan SHE
%A Xiaoran XU
%A Yixin LIU
%A Xinyu WANG
%A Sheng TIAN
%A Shiyi LI
%A Miao WANG
%A Chaochao YU
%A Pan LIU
%A Tianhe HUANG
%A Yongchang WEI
%J Journal of Zhejiang University SCIENCE B
%P 232-247
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B2200351"

TY - JOUR
T1 - AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer
A1 - Yi LI
A1 - Wenyan SHE
A1 - Xiaoran XU
A1 - Yixin LIU
A1 - Xinyu WANG
A1 - Sheng TIAN
A1 - Shiyi LI
A1 - Miao WANG
A1 - Chaochao YU
A1 - Pan LIU
A1 - Tianhe HUANG
A1 - Yongchang WEI
J0 - Journal of Zhejiang University Science B
SP - 232
EP - 247
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
ER -
doi="https://doi.org/10.1631/jzus.B2200351"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-‍(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.

AAZ2可通过靶向PDK1介导线粒体依赖的凋亡

李怡¹, 佘文妍², 徐笑然¹, 刘艺欣¹, 王新宇¹, 田胜¹, 李世毅¹, 王淼¹, 余超超³, 刘攀¹, 黄天河¹, 魏永长¹
¹武汉大学中南医院放化疗科，湖北省肿瘤医学临床研究中心，肿瘤生物学行为湖北省重点实验室，中国武汉， 430071
²武汉大学化学与分子科学学院，中国武汉， 430071
³武汉大学中南医院中西医结合科，中国武汉， 430071
概要：大部分化疗药物可以促进活性氧（ROS）产生，同时ROS可以诱导细胞凋亡。本研究构建了一种有机砷化合物N-(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide（AAZ2），其可通过促进ROS产生诱导胃癌线粒体依赖的细胞凋亡。具体机制为AAZ2通过靶向丙酮酸脱氢酶激酶1（PDK1）导致葡萄糖代谢改变和氧化应激，继而抑制PI3K/AKT/mTOR通路，最终激活半胱天冬酶（caspase）依赖的细胞凋亡。此外，体内实验也证实了AAZ2可以抑制胃癌移植瘤的生长。综上，在胃癌中，AAZ2可以通过靶向PDK1影响葡萄糖代谢及随后的氧化应激反应，抑制PI3K/AKT/mTOR信号通路，最终诱发线粒体依赖的细胞凋亡。

关键词组：AAZ2；胃癌；活性氧（ROS）；细胞凋亡；丙酮酸脱氢酶激酶1（PDK1）；葡萄糖代谢

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AAZ2可通过靶向PDK1介导线粒体依赖的凋亡

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