title: Pyruvate kinase M2 accelerates pro-inflammatory cytokine secretion and cell proliferation induced by lipopolysaccharide in colorectal cancer.
abstract: Surgery-induced inflammation has been associated with cancer recurrence and metastasis in colorectal cancer (CRC). As a constituent of gram-negative bacteria, lipopolysaccharide (LPS) is frequently abundant in the peri-operative window. However, the definite roles of LPS in tumour progression remain elusive. Here we reported that LPS treatment increased PKM expression through activation of NF-κB signalling pathway, and knockdown of PKM reversed LPS-induced TNF-α, IL-1β production and cell proliferation in CRC cells. We further showed that the PKM2 but not PKM1 mediated the pro-inflammatory and proliferative effects of LPS. Interestingly, LPS promoted PKM2 binding to the STAT3 promoter to enhance STAT3 expression and its subsequent nuclear translocation. Depletion of STAT3 decreased PKM2-induced TNF-α and IL-1β expression, indicating that STAT3 mediates the pro-inflammatory effects of PKM2. Furthermore, it is the protein kinase activity but not the pyruvate kinase activity of PKM2 that is required for inflammatory cytokine production. Collectively, our findings reveal the NF-κB-PKM2-STAT3 axis as a novel mechanism for the regulation of TNF-α and IL-1β production and suggest the importance of PKM2 as a key inflammatory mediator in inflammatory microenvironment.
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: College of Life Science, Shanxi University, Taiyuan 030006, China.
authors.forename: Hanqing
authors.initials: H
authors.lastname: Li
authors.affiliation: College of Life Science, Shanxi University, Taiyuan 030006, China.
authors.forename: Yangxu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
authors.forename: Haili
authors.initials: H
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China; College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: lzy@sxu.edu.cn.
authors.forename: Zhuoyu
authors.initials: Z
authors.lastname: Li
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D053583:Interleukin-1beta / Q000032:analysis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D011770:Pyruvate Kinase
keywords: Inflammation; LPS; PKM1; PKM2; Proliferation; STAT3