Key roles of necroptotic factors in promoting tumor growth
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Xinjian Liu1,2, Min Zhou1,3, Ling Mei4,5,6,7, Jiaying Ruan4,5,6,7, Qian Hu4,5,6,7, Jing Peng4,5,6,7, Hang Su4,5,6,7, Hong Liao4,5,6,7, Shanling Liu4,5,6, WeiPing Liu8, He Wang4,5,6, Qian Huang2, Fang Li1, Chuan-Yuan Li1,9
1Department of Dermatology, Duke University Medical Center, Durham, North Carolina 27710, USA
2Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, China
3State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China
4Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
5MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
6Laboratory 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
7Laboratory of Genetics, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
8Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
9Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
Chuan-Yuan Li, e-mail: [email protected]
Keywords: necroptosis, RipK1, RipK3, MLKL, tumor growth
Received: January 25, 2016 Accepted: February 23, 2016 Published: March 5, 2016
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.
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