How to switch from apoptotic to necroptotic cell death? Answer: Autophagy!

By Christina Towers, PhD.

It has long been known that programmed cell death can take place in many forms.  The most well characterized form, apoptosis, occurs when either extrinsic or intrinsic stimuli stimulate signaling cascades that result in a series of caspase cleavage events resulting in cleavage and activation of the effector caspase-3.  The end result is cell shrinkage, condensation and cleavage of chromosomal DNA, and plasma membrane blebbing that leaves the cell membrane intact¹.  Apoptotic cells are engulfed by antigen presenting cells and induce anti-inflammatory and tolerogenic immune responses².  Alternatively, necroptosis, a programmed form of necrosis, is less characterized.  However, it is now known that this process is also tightly regulated and mediated by a complex of proteins that make up the necrosome and include RIPK1, RIPK3, and MLKL.  Unlike apoptosis, necroptosis is characterized by the absence of caspase cleavage.  Perhaps the most impactful difference between these two, are their elicited immune responses.  In contrast to apoptosis, necroptosis can be characterized by the emission of DAMPs and cytokines that promote a pro-inflammatory response that is immunogenic². These stark differences suggest that new targeted cancer therapeutics could be improved upon if they induce necroptosis as opposed to apoptosis, employing the body’s immune response to actively participate in tumor clearance.  So how can researchers design therapeutics that mediate this switch from apoptotic cell death to necroptotic cell death?

A recent publication in the journal Development Cell by Goodall et al identifies a mechanism that may be the answer: autophagy³.  The authors show that in a necroptotic-prone system the autophagy cargo protein, p62, can regulate the switch between apoptotic and necroptotic cell death.  With the use of dual proximity ligation assays (PLA), co-immunoprecipitations, and immune-gold transmission electron microscopy the authors show that the necrosome complex forms on the autophagosome in a p62 dependent manner.  Interestingly, they show that late stage autophagy inhibitors increase necroptosis, however inhibition of early stage autophagy, specifically the formation of autophagosomes inhibits necroptosis.  Moreover, specific knock down of p62 switches the primary mode of cell death from necroptosis to apoptosis. Their model hypothesizes that the autophagosome acts as a scaffold for the necrosome, while the degradative properties of autophagy are not as relevant for this signaling. The results published in this manuscript are restricted to a specific cellular context: TRAIL or TNFα induced cell death in necroptotic-prone cells that have lost MAP3K7, a gene lost in 30-40% of prostate cancers and whose loss correlates with aggressive disease.  Even if these results prove to be restricted to this specific context, these data suggest that late stage autophagy inhibitors in combination with apoptotic inducing drugs like TRAIL could increase tumor shrinkage and patient outcome by inducing immunogenic necroptosis, while early stage autophagy inhibitors would not be as effective.  The results presented here strongly suggest that this will be true in MAP3k7-null prostate cancer, however, more studies need to be done to identify how generalizable these effects may be in other tumor types and subtypes and with other death inducing stimuli.

Explore Necroptosis Interactive Pathway

Christina Towers, PhD

References

1. Elmore, S. Apoptosis: a review of programmed cell death. Toxicol Pathol 35, 495-516, doi:10.1080/01926230701320337 (2007).
2. Krysko, O. et al. Necroptotic cell death in anti-cancer therapy. Immunol Rev 280, 207-219, doi:10.1111/imr.12583 (2017).
3. Goodall, M. L. et al. The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis. Dev Cell 37, 337-349, doi:10.1016/j.devcel.2016.04.018 (2016).