Pyroptosis: A new frontier in cancer

Fang, Yuan; Tian, Shasha; Pan, Yongsheng; Li, Wei; Wang, Qiming; Tang, Yu; Yu, Tao; Wu, Xi; Shi, Yongkang; Ma, Pei; Shu, Yongqian

doi:10.1016/j.biopha.2019.109595

Cited by 754 publications

(655 citation statements)

References 103 publications

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“…Pyroptosis can be triggered by the N-terminal domain of GSDMD due to cleavage by caspase-1/-4/-5/-11 (33). However, in our study, GSDMD was not shown to be cleaved in response to oxaliplatin and GW4064 alone or in combination ( Fig.…”

Section: Gsdme-dependent Pyroptosis Is Downstream Of the Bax-mitochoncontrasting

confidence: 52%

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

Guo

Zheng

et al. 2020

Preprint

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Background Repeated and long-term oxaliplatin therapy leads to drug resistance and severe adverse events, which limit its clinical use. These difficulties highlight the importance of identifying potent and specific drug combinations to enhance the antitumor effects of oxaliplatin. The farnesoid X receptor (FXR) deficiency in colorectal cancer (CRC) suggests that restoring FXR function might be a promising strategy for CRC treatment.Methods A series of in vitro and in vivo experiments were conducted to assess the antitumor effect of the combination of oxaliplatin and FXR agonist GW4064 in CRC. The synergistic mechanism involved was explored.Results A drug combination study showed that the GW4064 acted synergistically with oxaliplatin in colon cancer cells. The combination of oxaliplatin plus GW4064 inhibited cell growth and colony formation, induced apoptosis and pyroptosis in vitro, and slowed tumor growth in vivo. Mechanistically, GW4064 enhanced the chemosensitivity of cells to oxaliplatin by inducing BAX/caspase-3/GSDME-mediated pyroptosis. Furthermore, the combination of oxaliplatin and GW4064 synergistically inhibited STAT3 signaling by restoring SHP expression.Conclusions Our study revealed that GW4064 could enhance the antitumor effects of oxaliplatin against CRC, which provides a novel therapeutic strategy based on a combinational approach for CRC treatment.

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Section: Gsdme-dependent Pyroptosis Is Downstream Of the Bax-mitochoncontrasting

confidence: 52%

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

Guo

Zheng

et al. 2020

Preprint

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“…Cancer is a complex multifactorial disease with a high global mortality and a serious threat to human health. In addition, it is the principle death reasons in the developing countries and the second leading cause of death in the developed countries 1 . Its occurrence is mainly caused by abnormal cell growth which is induced by activation of proto-oncogene and inactivation of tumor suppressor gene.…”

Section: Introductionmentioning

confidence: 99%

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

et al. 2020

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Apoptosis has long been recognized as a mechanism that kills the cancer cells by cytotoxic drugs. In recent years, studies have proved that pyroptosis can also shrink tumors and inhibit cells proliferation. Both apoptosis and pyroptosis are caspase-dependent programmed cell death pathways. Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death. When GSDME is highly expressed, the active caspase-3 cuts it and releases the N-terminal domain to punch holes in the cell membrane, resulting in cell swelling, rupture, and death. When the expression of GSDME is low, it will lead to the classical mechanism of tumor cell death, which is apoptosis. More interestingly, researchers have found that GSDME can also be located upstream of caspase-3, connecting extrinsic, and intrinsic apoptotic pathways. Then, promoting caspase-3 activation, and forming a self-amplifying feed-forward loop. GSDME-mediated pyroptosis is correlated with the side effects of chemotherapy and anti-tumor immunity. This article mainly reviews the caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer, to provide new strategies and targets for cancer treatment.

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“…In brief, pyroptosis is a form of in ammatory programmed cell death characterized by in ammasome activation, membrane poreformation, swelling, rupture, and ultimate dissolution and release of intracellular contents [51]. In the canonical in ammasome pathway, NLRP3 in ammasomes are activated to recruit ASC to form ASC focus [51,52]. Then, ASC focus activated Caspase-1, which cleaves pro-IL-18/1β and gasdermin D (GSDMD) to release their mature forms [51].…”

Section: Discussionmentioning

confidence: 99%

Betulinic Acid Inhibits ROS-Mediated Pyroptosis in Spinal Cord Injury by Augmenting Autophagy via the AMPK-mTOR-TFEB Signaling Pathway

Chen

Zhuang

et al. 2020

Preprint

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Background：Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. Methods：Using a mouse model of SCI, survival and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, and pyroptosis; ROS- and AMPK-related signaling pathways were also examined. Results：Our results showed that BA significantly improves functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS-activity and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induces mitophagy to eliminate the accumulation of ROS and subsequently inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Conclusion: BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.

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Pyroptosis: A new frontier in cancer

Cited by 754 publications

References 103 publications

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

Betulinic Acid Inhibits ROS-Mediated Pyroptosis in Spinal Cord Injury by Augmenting Autophagy via the AMPK-mTOR-TFEB Signaling Pathway

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