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Updated: Jun 12, 2026
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
Mechanistic analysis of MLKL-driven cell survival
Peijia Jiang1, Xiaoyang Liu2, Mauricio J Reginato3
1Departments of Pediatrics & Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
Abstract:
MLKL pseudokinase is a critical executioner of necroptotic cell death. MLKL drives necroptosis by forming pores in the cell membrane. A growing body of data indicates that, in addition to this well-established role, MLKL can promote cell survival in certain contexts. Moreover, pharmacological or genetic MLKL inhibition was shown to suppress in vivo growth of several tumor types. It was found that MLKL protects cancer cells from various cell death-inducing stimuli by promoting autophagy or preserving the mitochondrial function of the cells. It was proposed that both of these MLKL effects prevent parthanatos, a cell death type mediated by hyperactivation of PARP1 and subsequent PARP1-dependent chromosomal DNA degradation. In addition, MLKL was found to protect tumor cells from the death receptor-induced demise and trigger the secretion of the growth-promoting cytokines by the cells. Notably, MLKL-deficient mice are healthy, while pharmacological MLKL inhibitors are not significantly toxic to mice. Hence, targeting MLKL in vivo to block MLKL-dependent cancer cell survival is feasible. The mechanisms of the pro-survival MLKL effects is the subject of this review.
Insights
The mixed lineage kinase domain-like protein (MLKL) executes necroptosis but also promotes cancer cell survival. Targeting MLKL could be a viable strategy to inhibit tumor growth by blocking these pro-survival effects.
Area of Science:
- Cell Biology
- Molecular Oncology
- Immunology
Background:
- The mixed lineage kinase domain-like protein (MLKL) is a key mediator of programmed necrosis (necroptosis) by forming pores in cell membranes.
- Emerging evidence suggests MLKL possesses pro-survival functions in cancer cells, counteracting various cell death pathways.
Purpose of the Study:
- This review focuses on elucidating the multifaceted mechanisms through which MLKL promotes cancer cell survival.
- To explore the therapeutic potential of targeting MLKL's pro-survival roles in cancer treatment.
Main Methods:
- The review synthesizes findings from preclinical studies investigating MLKL's role in cancer.
- Analysis of data on MLKL's interactions with autophagy, mitochondrial function, and cell death signaling pathways.
- Examination of in vivo studies involving MLKL inhibition in tumor models.
Main Results:
- MLKL protects cancer cells from death stimuli by enhancing autophagy and maintaining mitochondrial integrity.
- MLKL's pro-survival actions may prevent parthanatos, a cell death pathway involving PARP1.
- MLKL also confers resistance to death receptor-mediated apoptosis and promotes secretion of tumor-promoting cytokines.
Conclusions:
- MLKL exhibits dual roles in necroptosis execution and cancer cell survival.
- Targeting MLKL presents a promising therapeutic strategy for various cancer types, as MLKL inhibition has shown efficacy in preclinical models.
- Pharmacological inhibition of MLKL is a feasible in vivo approach with minimal toxicity observed in mice.
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