title: Key roles of necroptotic factors in promoting tumor growth.
abstract: Necroptotic factors are generally assumed to play a positive role in tumor therapy by eliminating damaged tumor cells. Here we show that, contrary to expectation, necroptotic factors RIPK1, RIPK3, and MLKL promote tumor growth. We demonstrate that genetic knockout of necroptotic genes RIPK1, RIPK3, or MLKL in cancer cells significantly attenuated their abilities to grow in an anchorage-independent manner. In addition, they exhibited significantly enhanced radiosensitivity. The knockout cells also showed greatly reduced ability to form tumors in mice. Moreover, necrosulfonamide (NSA), a previously identified chemical inhibitor of necroptosis, could significantly delay tumor growth in a xenograft model. Mechanistically, we show that necroptoic factors play a significant role in maintaining the activity of NF-κB. Finally, we found that high levels of phosphorylated MLKL in human esophageal and colon cancers are associated with poor overall survival. Taken together, we conclude that pro-necroptic factors such as RIPK1, RIPK3, and MLKL may play a role in supporting tumor growth, and MLKL may be a promising target for cancer treatment.
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina 27710, USA.|Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina 27710, USA.|State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Genetics, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Genetics, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Genetics, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Genetics, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Genetics, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Genetics, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.affiliation: Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Shanling
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: WeiPing
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.|Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Chuan-Yuan
authors.initials: CY
authors.lastname: Li
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055786:Gene Knockout Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D009336:Necrosis / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; C570695:N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide; D013449:Sulfonamides; C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: MLKL; RipK1; RipK3; necroptosis; tumor growth