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Quercetin-induced pyroptosis in colon cancer through NEK7-mediated NLRP3 inflammasome-GSDMD signaling pathway
Shi-Han Feng1, Bin Zhao1, Xue Zhan2
1Department of Traditional Chinese Medicine, Yong Chuan Hospital of Chongqing Medical University, Chongqing Medical University Chongqing 402160, P. R. China.
Abstract:
Pyroptosis, a gasdermin-mediated lytic cell death, is a new hotspot topic in cancer research, and induction of tumor pyroptosis has emerged as a new target in cancer management. Quercetin (Que), a natural substance, demonstrates promising anticancer action. However, further information is required to fully comprehend the function and mechanism of Que in pyroptosis in colon cancer. This study revealed the underlying mechanism of Que-induced pyroptosis in colon cancer in vitro and in vivo. Que inhibited colon cancer cell growth through gasdermin D (GSDMD)-mediated pyroptosis. Depletion of GSDMD, rather than gasdermin E (GSDME), reversed the cytotoxic effects of Que on colon cancer cells. Que treatment upregulated NIMA-related kinase 7 (NEK7) protein expression, thus facilitating the assembly of the NLRP3 inflammasome and cleavage of GSDMD. NEK7 silencing resulted in colon cancer cell growth in vitro and in vivo. Mechanistically, NEK7 depression restrained the activation of the NLRP3 inflammasome-GSDMD pathway, thus attenuating pyroptosis triggered by Que in colon cancer cells. Furthermore, lower NEK7 and NLRP3 expression levels indicated colon cancer progression. Our results unveiled a novel pattern of anti-colon cancer activity of Que, and activation of NEK7-mediated pyroptosis is potentially a promising therapeutic target for colon cancer, which provides novel experimental proof for the clinical application of Que.
Insights
Quercetin (Que) inhibits colon cancer by triggering gasdermin D (GSDMD)-mediated pyroptosis. This process involves NIMA-related kinase 7 (NEK7) activating the NLRP3 inflammasome, offering a new therapeutic target for colon cancer.
Area of Science:
- Oncology
- Cell Death Research
- Molecular Biology
Background:
- Pyroptosis, a lytic cell death pathway, is a key area in cancer research.
- Inducing tumor pyroptosis is a novel strategy for cancer management.
- Quercetin (Que) shows potential anticancer properties, but its role in colon cancer pyroptosis needs clarification.
Purpose of the Study:
- To elucidate the mechanism of Que-induced pyroptosis in colon cancer.
- To investigate the role of gasdermin D (GSDMD) and NIMA-related kinase 7 (NEK7) in Que's anti-colon cancer effects.
Main Methods:
- In vitro and in vivo studies were conducted on colon cancer models.
- Gene silencing techniques were used to deplete GSDMD and NEK7.
- Protein expression levels of NEK7, NLRP3, and GSDMD cleavage were analyzed.
Main Results:
- Que inhibited colon cancer cell growth via GSDMD-mediated pyroptosis.
- GSDMD, not GSDME, was crucial for Que's cytotoxic effects.
- Que upregulated NEK7, promoting NLRP3 inflammasome assembly and GSDMD cleavage.
- NEK7 silencing hindered Que-induced pyroptosis and promoted tumor growth.
- Lower NEK7 and NLRP3 expression correlated with colon cancer progression.
Conclusions:
- Que exerts anti-colon cancer effects by activating NEK7-mediated pyroptosis through the NLRP3-GSDMD pathway.
- NEK7-mediated pyroptosis is a potential therapeutic target for colon cancer.
- Que's anti-cancer activity provides experimental support for its clinical use in colon cancer.
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