Oncotarget

Research Papers:

Neoalbaconol induces cell death through necroptosis by regulating RIPK-dependent autocrine TNFα and ROS production

Xinfang Yu, Qipan Deng, Wei Li, Lanbo Xiao, Xiangjian Luo, Xiaolan Liu, Lifang Yang, Songling Peng, Zhihui Ding, Tao Feng, Jian Zhou, Jia Fan, Ann M. Bode, Zigang Dong, Jikai Liu _ and Ya Cao

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Oncotarget. 2015; 6:1995-2008. https://doi.org/10.18632/oncotarget.3038

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Abstract

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.


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