title: Necrostatin-1 reduces intestinal inflammation and colitis-associated tumorigenesis in mice.
abstract: Necroptosis, a novel form of programmed cell death, was recently shown to be strongly associated with intestinal inflammation in mice and in pediatric patients with inflammatory bowel disease (IBD). Persistent inflammation of the colon is an important risk factor for colorectal cancer. Necrostatin-1 (Nec-1), known as a specific inhibitor of necroptosis, through preventing the receptor-interacting protein (RIP) 1 and RIP3 interaction. In the present study, the anti-inflammatory and antitumorigenic efficacy of necrostatin-1 was studied in mouse models of colitis and colitis-associated cancer (CAC). We found that in acute dextran sulfate sodium (DSS)-induced colitis, treatment with necrostatin-1 significantly suppressed colitis symptoms in mice, including weight loss, colon shortening, colonic mucosa damage and severity, and excessive production of interleukin-6. Necrostatin-1 administration inhibited the upregulation of RIP1 and RIP3 and enhanced the expression of caspase-8 in DSS-induced colitis. In addition, the anti-inflammatory effect of necrostatin-1 was confirmed by in vitro analyses. Necrostatin-1 treatment reduced the production of proinflammatory cytokine and extracellular HMGB1 release in HT-29 cells in active necroptosis. Furthermore, In a mouse model of colitis-associated tumorigenesis, necrostatin-1 administration significantly suppressed tumor growth and development through inhibiting JNK/c-Jun signaling. Taken together, these findings suggest that necrostatin-1 might be a promising therapeutic option for the treatment of colitis-associated colorectal cancer in patients with IBD.
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Yun-Shan
authors.initials: YS
authors.lastname: Guo
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Zhou
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Zhi-Guang
authors.initials: ZG
authors.lastname: Fu
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Bao-Qing
authors.initials: BQ
authors.lastname: Xu
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Jiang-Hua
authors.initials: JH
authors.lastname: Li
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Jing
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Jian-Li
authors.initials: JL
authors.lastname: Jiang
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University Xi'an, China.
authors.forename: Zhi-Nan
authors.initials: ZN
authors.lastname: Chen
keywords: Inflammatory bowel diseases; colon cancer; murine colitis models; necroptosis; necrostatin-1