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Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway
Joint Authors
Wang, Yifei
Hu, Liubing
Wang, Yan
Chen, Zui
Fu, Liangshun
Wang, Sheng
Zhang, Xinyue
Zhang, Pengchao
Lu, Xueping
Jie, Huiyang
Li, Manmei
Liu, Zhong
Source
Oxidative Medicine and Cellular Longevity
Issue
Vol. 2019, Issue 2019 (31 Dec. 2019), pp.1-26, 26 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2019-03-25
Country of Publication
Egypt
No. of Pages
26
Main Subjects
Abstract EN
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells.
However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies.
Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed.
In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells.
Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic.
Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells.
Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53.
ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53.
Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells.
The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL.
In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells.
The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5.
Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway.
Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.
American Psychological Association (APA)
Hu, Liubing& Wang, Yan& Chen, Zui& Fu, Liangshun& Wang, Sheng& Zhang, Xinyue…[et al.]. 2019. Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway. Oxidative Medicine and Cellular Longevity،Vol. 2019, no. 2019, pp.1-26.
https://search.emarefa.net/detail/BIM-1206528
Modern Language Association (MLA)
Hu, Liubing…[et al.]. Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway. Oxidative Medicine and Cellular Longevity No. 2019 (2019), pp.1-26.
https://search.emarefa.net/detail/BIM-1206528
American Medical Association (AMA)
Hu, Liubing& Wang, Yan& Chen, Zui& Fu, Liangshun& Wang, Sheng& Zhang, Xinyue…[et al.]. Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway. Oxidative Medicine and Cellular Longevity. 2019. Vol. 2019, no. 2019, pp.1-26.
https://search.emarefa.net/detail/BIM-1206528
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1206528