title: Dietary cholesterol promotes AOM-induced colorectal cancer through activating the NLRP3 inflammasome.
abstract: Prolonged ingestion of a cholesterol-enriched diet induces chronic, auto-inflammatory responses resulting in significant health problems including colorectal cancer. Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to inflammatory bowel diseases and colitis-associated cancer (CAC). However, in vitro and in vivo information regarding the inflammation-inducing and tumor-promoting effect of cholesterol is lacking. Here we show that the cholesterol promoted colon carcinogenesis in azoxymethane (AOM)-treated mice through activating the NLRP3 inflammasome. High cholesterol diet (HCD) significantly increased inflammatory responses and tumor burden. Cholesterol crystals, detected in the colon of mice fed with HCD, also promoted NLRP3 inflammasome activation in macrophages, as indicated by elevated expression of cleaved caspase-1, formation of NLRP3-ASC-caspase-1 complex assembly, and higher IL-1β secretion. Importantly, cholesterol was found to inhibit the activity of AMPKα in macrophages, leading to a significant production of mitochondrial ROS, which in turn activated the NLRP3 inflammasome. Moreover, crystal uptake and cathepsin B accounted for cholesterol crystal-induced inactivation of AMPKα. Finally, HCD-induced increase in IL-1β secretion, macrophage infiltration and tumor burden was diminished by the deletion of NLRP3 in AOM-treated mice. Taken together, our findings demonstrate that the pro-inflammatory and cancer-promoting effects of HCD are mediated by the activation of NLRP3 inflammasome. Our study extended our knowledge on how dietary choices can influence processes involved in chronic inflammatory disorders and colorectal cancer.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China; General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, China.
authors.forename: Qianming
authors.initials: Q
authors.lastname: Du
authors.affiliation: Department of Neurosurgery, Wuxi Second Hospital Affiliated Nanjing Medical University, Wuxi 214002, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Fan
authors.affiliation: Neurobiology Laboratory, Jiangsu Center for Drug Screening, China Pharmaceutical University, Jiangsu, Nanjing 210009, China.
authors.forename: Jianing
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China.
authors.forename: Xiuting
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China. Electronic address: cpuwyj@cpu.edu.cn.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China. Electronic address: ronghu@cpu.edu.cn.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D015179:Colorectal Neoplasms / Q000139:chemically induced* / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002791:Cholesterol, Dietary; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D001397:Azoxymethane
keywords: Cholesterol; Colorectal cancer; Inflammation; Mitochondrial ROS; NLRP3 inflammasome