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

// 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 6 , Jia Fan 6 , Ann M. Bode 5 , Zigang Dong 5 , Jikai Liu 4 and Ya Cao 1,2,3 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.