Cancer therapy in the necroptosis era

Abstract

Necroptosis is a caspase-independent form of regulated cell death executed by the receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). Recently, necroptosis-based cancer therapy has been proposed to be a novel strategy for antitumor treatment. However, a big controversy exists on whether this type of therapy is feasible or just a conceptual model. Proponents believe that because necroptosis and apoptosis use distinct molecular pathways, triggering necroptosis could be an alternative way to eradicate apoptosis-resistant cancer cells. This hypothesis has been preliminarily validated by recent studies. However, some skeptics doubt this strategy because of the intrinsic or acquired defects of necroptotic machinery observed in many cancer cells. Moreover, two other concerns are whether or not necroptosis inducers are selective in killing cancer cells without disturbing the normal cells and whether it will lead to inflammatory diseases. In this review, we summarize current studies surrounding this controversy on necroptosis-based antitumor research and discuss the advantages, potential issues, and countermeasures of this novel therapy.

Figure 1

Necroptotic pathway. Necroptosis can be triggered by engagement of TNF-α to TNF receptor superfamily (e.g. TNFR, Fas, and DR4/DR5), Toll-like receptors (e.g. TLR3 and TLR4), T-cell receptors, interferon receptors, cellular metabolic and genotoxic stresses, or some anticancer compounds. RIP1–RIP3–MLKL complex, also called ‘necrosome', is a critical mediator of the necroptotic pathway that bridges the signals of upstream cell death receptors (or other receptors) and downstream executing molecules and events, such as plasma membrane permeabilization, cytosolic ATP reduction, and reactive oxygen species (ROS) burst. In TNF-α-induced necroptosis, TNF binds to the TNF receptors and engages a big complex formation called Complex I, which includes cIAP1, cIAP2, CYLD, RIP1, and TRAF2. cIAPs induce RIP1 polyubiquitination to inhibit Complex IIa in which caspase-8, FADD, and RIP1 are involved, and Complex IIb, comprising the caspase-8, FADD, RIP1, RIP3, MLKL formation, thus blocking RIP1-mediated apoptosis or necroptosis. In addition, polyubiquitinated RIP1 recruits NEMO and TAB2 that mediate NF-κB activation and MAPKs (i.e. ERK, JNK, p38) activation, respectively. Unlike the RIP1 polyubiquitination that benefit cell survival, CYLD deubiquitinates RIP1 and promotes the packaging of Complexes IIa and IIb. In the Complex IIa, activated caspase-8 cleaves and abolishes the activities of RIP1, RIP3, and CYLD, thus blocking necroptosis. However, when the cleavage of RIP1 and RIP3 is prevented by caspase-8 inhibitors (e.g., zVAD) or by the genetic deletion of caspase-8 or FADD, the Complex IIb forms and initiates necroptosis. Necroptosis can be pharmacologically inhibited by Nec-1 (RIP1 kinase inhibitor), GSK-843/-872 (RIP3 kinase inhibitor), and necrosulfonamide (NSA, MLKL inhibitor). TNFR1, TNF receptor 1; NEMO, IKK-γ; DR4/5, death receptor 4 or 5; TLRs, toll-like receptors; TCR, T-cell receptor; TAK1, transforming growth factor-β-activated kinase 1; TAB2, TAK1-binding protein 2; TRIF, Toll/IL-1 receptor domain-containing adaptor-inducing interferon-β

Figure 2

A diagram illustrating the pronecroptotic cancer therapy