Research Papers:
Neoalbaconol induces cell death through necroptosis by regulating RIPKdependent autocrine TNFα and ROS production
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Xinfang Yu1,2,3,*, Qipan Deng1,2,3,*, Wei Li1,2,3, Lanbo Xiao1,2,3, Xiangjian Luo1,2,3, Xiaolan Liu1,2,3, Lifang Yang1,2,3, Songling Peng1,2,3, Zhihui Ding4, Tao Feng4, Jian Zhou6, Jia Fan6, Ann M. Bode5, Zigang Dong5, Jikai Liu4 and Ya Cao1,2,3
1 Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China
2 Key Laboratory of Chinese Ministry of Education, Central South University, Hunan, China
3 Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China
4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan, China
5 The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
6 Liver Cancer Institute, Liver Surgery Department, Zhongshan Hospital
* These authors contributed equally to this work
Correspondence:
Jikai Liu, email:
Ya Cao, email:
Keywords: necoalbaconol, necroptosis, RIPK, TNFα, NF-κB signaling pathway, ROS
Received: October 19, 2014 Accepted: December 02, 2014 Published: December 03, 2014
Abstract
Necroptosis/regulated necrosis is a caspase-independent, but receptor interacting protein kinase (RIPK)-dependent form of cell death. In previous studies, neoalbaconol (NA), a constituent extracted from Albatrellus confluens, was demonstrated to induce necroptosis in some cancer cell lines. The molecular mechanism of NA-induced necroptosis is described in this research study. We determined that NA-induced cell death is partly dependent on tumor necrosis factor α (TNFα) feed-forward signaling. More importantly, NA abolished the ubiquitination of RIPK1 by down-regulating E3 ubiquitin ligases, cellular inhibitors of apoptosis protein 1/2 (cIAP1/2) and TNFα receptor-associated factors (TRAFs). The suppression of RIPK1 ubiquitination induced the activation of the non-canonical nuclear factor-κB (NF-κB) pathway and stimulated the transcription of TNFα. Moreover, we also found that NA caused RIPK3-mediated reactive oxygen species (ROS) production and contribution to cell death. Taken together, these results suggested that two distinct mechanisms are involved in NA-induced necroptosis and include RIPK1/NF-κB-dependent expression of TNFα and RIPK3-dependent generation of ROS.