Cancer and necroptosis: friend or foe?

Abstract

Regulated cell death is one major factor to ensure homoeostasis in multicellular organisms. For decades, apoptosis was considered as the sole form of regulated cell death, whereas necrosis was believed to be accidental and unregulated. Due to this view, research on necrosis was somewhat neglected, especially in the field of anti-cancer treatment. However, new interest in necrosis has been sparked by the recent discovery of different forms of necrosis that show indeed regulated pathways. More and more studies now address the molecular pathways of regulated necrosis and its connections within the cellular signaling networks. Necroptosis, a subform of regulated necrosis, has so far hardly been focused on with regard to a future treatment of cancer patients and may emerge as a novel and effective approach to eliminate tumor cells. However, and similar to apoptosis, tumor cells can develop resistances against necroptosis to ensure their own survival. In this context, new molecules that enhance necroptosis are currently being identified to overcome such resistances. This review discusses cancer and necroptosis as friends or foes, i.e. the options to exploit necroptosis in anti-cancer therapies ("foes"), but also potential limitations that may block or actually cause necroptosis to act in a protumoral manner ("friends"). The balance between these two possible roles will determine whether necroptosis can indeed be used as a promising tool for early diagnosis of tumors, prevention of metastasis and anti-cancer treatment.

Keywords: Cancer; Necroptosis; Regulated necrosis; TNF; TRAIL.

Fig. 1

Molecular pathway of necroptosis triggered by the family of death receptors. Upon caspase-8 inhibition (e.g. by caspase inhibitors such as zVAD-fmk), necroptosis is initiated by formation of the necrosome and subsequent phosphorylation of mixed lineage kinase domain like protein (MLKL). Necroptosis can be inhibited by pharmacological substances like necrostatin 1s (NEC1s) and necrosulfonamide (NSA)

Fig. 2

Schematic overview on the relationship of cancer and necroptosis as friend or foe. Events listed under “friend?” are beneficial for the survival of the whole tumor (e.g., induction of neovascularization) or for the survival of the individual cancer cell itself (e.g., downregulation/lack of key components of necroptosis). The induction of autophagy can further improve the invasion efficacy of metastatic cells by strengthening their fitness against necroptosis. Compounds that induce necroptosis in cancer cells or at least sensitize them for necroptosis are listed under “foe?”. In addition to those chemicals and naturally occurring substances, viral anti-apoptotic proteins (e.g., M45) and nanoparticles (e.g., ZnO and Ag) have also been shown to induce necroptosis in cancer cells. Since the sphingolipid ceramide has been reported as a key downstream mediator of necroptosis, the manipulation of intracellular sphingolipid levels may also represent a feasible target to induce necroptosis in cancer cells. The promotion of inflammatory responses by necroptosis may either be beneficial for the tumor (e.g., by promoting cancer cell spreading), or may contribute to a more efficient clearance of tumor cells by the immune system via the release of cytokines and DAMPs