PDF(Pubmed)
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.
摘要：
焦亡,gasdermin介导的裂解细胞死亡，是癌症研究的新热点,诱导肿瘤焦亡已成为癌症治疗的新目标。槲皮素（Que），一种天然物质，展示了有希望的抗癌作用。然而,需要更多的信息来充分了解Que在结肠癌中的功能和机制。这项研究揭示了Que诱导的结肠癌体内外焦凋亡的潜在机制。Que通过GasderminD（GSDMD）介导的焦亡抑制结肠癌细胞的生长。耗尽GSDMD，而不是gasderminE（GSDME），逆转Que对结肠癌细胞的细胞毒性作用。Que治疗上调NIMA相关激酶7（NEK7）蛋白表达，从而促进NLRP3炎性体的组装和GSDMD的裂解。NEK7沉默导致结肠癌细胞在体外和体内生长。机械上,NEK7抑郁症克制NLRP3炎性小体-GSDMD通路的激活,从而减弱由Que在结肠癌细胞中引发的焦亡。此外，较低的NEK7和NLRP3表达水平表明结肠癌进展.我们的研究结果揭示了Que抗结肠癌活性的新模式，激活NEK7介导的焦亡可能是结肠癌的一个有希望的治疗靶点，这为Que的临床应用提供了新的实验依据。
