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

  • Oncotarget. 2015 Feb 10;6(4):1995-2008. doi: 10.18632/oncotarget.3038.
Xinfang Yu  1  2  3 ,  Qipan Deng  1  2  3 ,  Wei Li  1  2  3 ,  Lanbo Xiao  1  2  3 ,  Xiangjian Luo  1  2  3 ,  Xiaolan Liu  1  2  3 ,  Lifang Yang  1  2  3 ,  Songling Peng  1  2  3 ,  Zhihui Ding  4 ,  Tao Feng  4 ,  Jian Zhou  5 ,  Jia Fan  5 ,  Ann M Bode  6 ,  Zigang Dong  6 ,  Jikai Liu  4 ,  Ya Cao  1  2  3
Affiliations
  • 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. Liver Cancer Institute, Liver Surgery Department, Zhongshan Hospital.
  • 6. The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
PMID: 25575821 DOI: 10.18632/oncotarget.3038
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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