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.
Highlights
Regulated cell death, a physiologic process for elimination of damaged cells, is critically important in normal development and disease pathogenesis
We discovered that NA triggers necroptosis by promoting autocrine secretion of tumor necrosis factor α (TNFα) through the regulation of the receptor interacting protein kinase (RIPK)/nuclear factor-κB (NF-κB) signaling pathway and RIPK3-dependent reactive oxygen species (ROS) production
NA induces the proteasomal degradation of cIAPs that leads to the de-ubiquitination of RIPK1 which activating necroptosome to initiate necroptosis; loss of cIAPs facilitates the stabilization of NF-κB inducing kinase (NIK), promoting IKKα/IKKα activation and the processing of p100 to p52 to activate non-canonical NF-κB pathway
Summary
A physiologic process for elimination of damaged cells, is critically important in normal development and disease pathogenesis. Multiple mechanisms of regulated cell death have been identified that function in distinct manners: apoptosis, autophagic cell death, and necrosis. Necroptosis is a form of regulated necrosis that is RIPK1/3-dependent under apoptotic deficient conditions [1]. Research results showed that a growing list of anticancer agents, such as etoposide [4], Smac mimetic [5, 6] and shikonin [7], can initiate necroptosis to kill cancer cells. These findings raised the possibility that necroptosis might be considered as an alternative choice for cancer treatment
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