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 Ar-(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.
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。
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This study was supported by the Wuhan University Zhongnan Hospital Translational Medicine and Interdisciplinary Research Joint Fund (No. ZNJC201910), China.
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Study design: Yi LI and Wenyan SHE; Data collection: Yi LI, Wenyan SHE, Xiaoran XU, Yixin LIU, Sheng TIAN, and Shiyi LI; Data analysis: Yi LI, Yixin LIU, and Xinyu WANG; Data interpretation: Yi LI, Wenyan SHE, Xinyu WANG, and Miao WANG; Writing of manuscript: Yi LI; Critical revision: Yi LI, Chaochao YU, and Pan LIU; Final approval: Yi LI, Yongchang WEI, and Tianhe HUANG; Overall supervision: Tianhe HUANG and Yongchang WEI. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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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, and Yongchang WEI declare that they have no conflict of interest.
The study was approved by the Medical Ethics Committee Zhongnan Hospital of Wuhan University (No. ZN2021006) and performed in accordance with the Declaration of Helsinki.
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Li, Y., She, W., Xu, X. et al. AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer. J. Zhejiang Univ. Sci. B 24, 232–247 (2023). https://doi.org/10.1631/jzus.B2200351
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DOI: https://doi.org/10.1631/jzus.B2200351
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