Lipopolysaccharide promotes metastasis via acceleration of glycolysis by the nuclear factor-κB/snail/hexokinase3 signaling axis in colorectal cancer

Abstract

Background Cancer cell is generally characterized by enhanced glycolysis. Inflammasome activation is interaction with glycolysis. The concentration of lipopolysaccharide (LPS), a classic inflammasome activator, is significantly higher in colorectal cancer tissue than in normal intestinal mucosa. However, the mechanism of LPS on glycolysis and metastasis has not been fully elucidated. This study aimed to investigate the roles of LPS on inflammasome activation, glycolysis, and metastasis, and unravel metformin’s potential in treatment of CRC. Methods We detected inflammasome activation and cell motility following LPS exposure in CRC cell lines. Glycolysis analysis was performed, and the key glycolytic rate-limiting enzymes were detected. Dual-luciferase reporter gene assay, co-immunoprecipitation, chromatin immunoprecipitation (ChIP) analysis, and ChIP-reChIP assay were performed to identify the specific mechanisms of LPS on glycolysis. Mouse metastasis models were used to determine the effects of LPS and metformin on metastasis. Correlation analysis of the expression of various molecules was performed in 635 CRC samples from The Cancer Genome Atlas and 83 CRC samples from our lab. Results LPS activates caspase-1 through NF-κB and upregulates the expression of Snail and HK3 depending on caspase-1 activation. LPS potentiates migration and invasion depending on accelerated glycolysis, which could be reversed by knockdown of glycolytic rate-limiting enzyme HK3. Nuclear Snail is upregulated by NF-κB under LPS treatment and then forms a complex with NF-κB, then directly binds to the HK3 promoter region to upregulate the expression of HK3. Metformin suppresses the NF-κB/Snail/HK3 signaling axis that is activated by LPS and then inhibits LPS-induced metastasis. In vivo, LPS-treated cells form more metastasis in the lungs of mice, and metformin completely reverses this effect of LPS. Conclusion LPS activates inflammasomes in cancer cells through NF-κB and promotes metastasis through glycolysis enhanced by the NF-κB/Snail/HK3 signaling pathway in CRC. Metformin could prevent this effect of LPS.

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“…al (2013) (33) they reported the oxidative stress and apoptosis inducing properties of LPS. It also been reported for promoting metastasis in cancer cells (34), (32). In this study, similar result with Halawa et.…”

“…In the present study antioxidative efficacy of OIM was tested in a LPS stimulated immunecompromise model of murine splenic macrophages. LPS a cellular component of gram negative bacteria is a classic inflammasome activator (32). In recent study, of Halawa et.…”

Microbiome analysis reveals universal diagnostic biomarkers for colorectal cancer across populations and technologies

“…LPS is a gram-negative bacterial antigen that activates TLR4 and induces immunosuppressive factors and apoptosis resistance, thereby promoting immune escape in human CRC cells ( Li et al, 2014 ). Wu et al have found that LPS accelerates glycolysis through the nuclear factor-κB/snail/hexokinase3 signaling axis to promote CRC metastasis ( Wu et al, 2021a ), and Liu et al have found that activation of p38 mitogen-activated protein kinase pathway by LPS aggravates postoperative intestinal obstruction in CRC patients ( Liu et al, 2022 ). Collectively, LPS might play an important role in the progression of CRC.…”

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