The role of necroptosis in cancer biology and therapy

Abstract

Apoptosis resistance is to a large extent a major obstacle leading to chemotherapy failure during cancer treatment. Bypassing the apoptotic pathway to induce cancer cell death is considered to be a promising approach to overcoming this problem. Necroptosis is a regulated necrotic cell death modality in a caspase-independent fashion and is mainly mediated by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis resistance and may trigger and amplify antitumor immunity in cancer therapy. The role of necroptosis in cancer is complicated. The expression of key regulators of the necroptotic pathway is generally downregulated in cancer cells, suggesting that cancer cells may also evade necroptosis to survive; however, in certain types of cancer, the expression level of key mediators is elevated. Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment. Necroptosis also reportedly promotes oncogenesis and cancer metastasis despite evidence demonstrating its antimetastatic role in cancer. In addition, necroptotic microenvironments can direct lineage commitment to determine cancer subtype development in liver cancer. A plethora of compounds and drugs targeting necroptosis exhibit potential antitumor efficacy, but their clinical feasibility must be validated. Better knowledge of the necroptotic pathway mechanism and its physiological and pathological functions is urgently required to solve the remaining mysteries surrounding the role of necroptosis in cancer. In this review, we briefly introduce the molecular mechanism and characteristics of necroptosis, the interplay between necroptosis and other cell death mechanisms, crosstalk of necroptosis and metabolic signaling and detection methods. We also summarize the intricate role of necroptosis in tumor progression, cancer metastasis, prognosis of cancer patients, cancer immunity regulation, cancer subtype determination and cancer therapeutics.

The Role of Autophagy in Pancreatic Cancer—Recent Advances

“…Autophagy supplies metabolites to sustain the energy needs of the cancer cells and provides energy for malignant transformation [3]. In addition to autophagy induction by low nutrient and oxygen levels, autophagy can also be induced by high levels of reactive oxygen species (ROS), for example those generated by necroptosis, a regulated necrotic cell death process [19]. In some cases, however, an increase in ROS levels induces cell death in PDAC cell lines, which coincides with lower autophagy levels.…”

“…A broad spectrum of cancers also rely on autophagy for survival in poorly oxygenated tumor areas, with data both in cell lines and xenograft models demonstrating that autophagy is required for cell survival under hypoxic conditions [21]. Autophagy may also prevent cell death by directly eliminating endogenous apoptosis inhibitors or creating an autophagosomal platform for caspase-8 activation [19]. A general theme that emerges from the study of autophagy in cancer is the existence of reciprocal relationships between autophagy and other cellular processes.…”

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

“…Necroptosis has been first described in 2005 as a caspase-independent cell death modality induced by perturbations of extra-or intra-cellular homeostasis when the apoptotic machinery is inhibited [125]. Necroptosis shares morphological features with necrosis, including membrane permeabilization, cell swelling and loss of cell integrity (Table 1), and in part, structural organization with extrinsic pathway of apoptosis ( Figure 3) [126]. Necroptosis is associated with a substantial production of reactive oxygen species (ROS), hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) and depletion of ATP [127,128].…”

“…Necroptosis is largely reliant on sequential activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) [5], and necrostatin-1 (Nec-1) and necrostatin-1s (Nec-1s), which selectively stabilize an inactive conformation of RIPK1, inhibit the necroptotic cell death pathway [129,130]. Mechanistically, necroptosis is activated by a plethora of different ligands, including tumor necrosis factor alpha (TNF-α), FAS ligand (FASL), TNF-related apoptosis-inducing ligand (TRAIL), interferon gamma (IFN-γ) and lipopolysaccharide (LPS) that engage members of the tumor necrosis factor receptor (TNFR) family, FAS, T cell receptors (TCRs), and pattern recognition receptors (PRRs) [126,131]. TNF-α-mediated necroptosis has been largely investigated so far ( Figure 3).…”

“…Activated RIPK1 interacts with RIPK3, and subsequently RIPK3 phosphorylates MLKL. MLKL is recruited to the plasma membrane, where it interacts with phospholipids to enhance membrane permeability and execute necroptosis ( Figure 3) [126,131]. The contribution of heat shock protein 90 (HSP90) to MLKL oligomerization and translocation has been ascribed [134,135].…”