Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production

Xiang-Liang Yuan, Yun-Lan Zhou, Wenjuan Wang, Junhua Li, Guohua Xie, Yan Zhao, Dakang Xu, Lisong Shen

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

Chronic infection, such as Helicobacter pylori infection, has been associated with the development of gastric cancer (GC). Pathogen-associated molecular patterns can trigger inflammatory responses via Toll-like receptors (TLRs) in GC. Here we showed that Toll-like receptor 4 (TLR4) was highly expressed in GC cells and was associated with the aggressiveness of GC. The binding of lipopolysaccharide (LPS) to TLR4 on GC cells enhanced proliferation without affecting apoptosis. Higher level of reactive oxygen species (ROS) was induced after activation of TLR4 signaling in GC. Using oxidase inhibitors and antioxidants, we found that mitochondrial ROS (mROS) was major source of TLR4-stimulated ROS generation. This elevated mROS production can be inhibited by diphenylene iodonium (DPI), and the blocking of the mROS production rather than ROS neutralization resulted in cell cycle arrest and the loss of mitochondrial potential, which were plausible reason for decreased cell viability. Furthermore, the increased mROS owing to TLR4 signaling resulted in the activation of Akt phosphorylation and NF-kappaB p65 nuclear translocation. Altogether, these results reveal a novel pathway linking innate immune signaling to GC cell proliferation, implicate mROS as an important component of cell survival signals and further establish mitochondria as hubs for GC therapies.
Original languageEnglish
Pages (from-to)1 - 10
Number of pages10
JournalCell Death and Disease
Volume4
Issue number9 (Article # e794)
DOIs
Publication statusPublished - 2013

Cite this

Yuan, X-L., Zhou, Y-L., Wang, W., Li, J., Xie, G., Zhao, Y., ... Shen, L. (2013). Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production. Cell Death and Disease, 4(9 (Article # e794)), 1 - 10. https://doi.org/10.1038/cddis.2013.334
Yuan, Xiang-Liang ; Zhou, Yun-Lan ; Wang, Wenjuan ; Li, Junhua ; Xie, Guohua ; Zhao, Yan ; Xu, Dakang ; Shen, Lisong. / Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production. In: Cell Death and Disease. 2013 ; Vol. 4, No. 9 (Article # e794). pp. 1 - 10.
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title = "Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production",
abstract = "Chronic infection, such as Helicobacter pylori infection, has been associated with the development of gastric cancer (GC). Pathogen-associated molecular patterns can trigger inflammatory responses via Toll-like receptors (TLRs) in GC. Here we showed that Toll-like receptor 4 (TLR4) was highly expressed in GC cells and was associated with the aggressiveness of GC. The binding of lipopolysaccharide (LPS) to TLR4 on GC cells enhanced proliferation without affecting apoptosis. Higher level of reactive oxygen species (ROS) was induced after activation of TLR4 signaling in GC. Using oxidase inhibitors and antioxidants, we found that mitochondrial ROS (mROS) was major source of TLR4-stimulated ROS generation. This elevated mROS production can be inhibited by diphenylene iodonium (DPI), and the blocking of the mROS production rather than ROS neutralization resulted in cell cycle arrest and the loss of mitochondrial potential, which were plausible reason for decreased cell viability. Furthermore, the increased mROS owing to TLR4 signaling resulted in the activation of Akt phosphorylation and NF-kappaB p65 nuclear translocation. Altogether, these results reveal a novel pathway linking innate immune signaling to GC cell proliferation, implicate mROS as an important component of cell survival signals and further establish mitochondria as hubs for GC therapies.",
author = "Xiang-Liang Yuan and Yun-Lan Zhou and Wenjuan Wang and Junhua Li and Guohua Xie and Yan Zhao and Dakang Xu and Lisong Shen",
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Yuan, X-L, Zhou, Y-L, Wang, W, Li, J, Xie, G, Zhao, Y, Xu, D & Shen, L 2013, 'Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production', Cell Death and Disease, vol. 4, no. 9 (Article # e794), pp. 1 - 10. https://doi.org/10.1038/cddis.2013.334

Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production. / Yuan, Xiang-Liang; Zhou, Yun-Lan; Wang, Wenjuan; Li, Junhua; Xie, Guohua; Zhao, Yan; Xu, Dakang; Shen, Lisong.

In: Cell Death and Disease, Vol. 4, No. 9 (Article # e794), 2013, p. 1 - 10.

Research output: Contribution to journalArticleResearchpeer-review

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