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MLKL in cancer: more than a necroptosis regulator

Abstract

Mixed lineage kinase domain-like protein (MLKL) emerged as executioner of necroptosis, a RIPK3-dependent form of regulated necrosis. Cell death evasion is one of the hallmarks of cancer. Besides apoptosis, some cancers suppress necroptosis-associated mechanisms by for example epigenetic silencing of RIPK3 expression. Conversely, necroptosis-elicited inflammation by cancer cells can fuel tumor growth. Recently, necroptosis-independent functions of MLKL were unraveled in receptor internalization, ligand-receptor degradation, endosomal trafficking, extracellular vesicle formation, autophagy, nuclear functions, axon repair, neutrophil extracellular trap (NET) formation, and inflammasome regulation. Little is known about the precise role of MLKL in cancer and whether some of these functions are involved in cancer development and metastasis. Here, we discuss current knowledge and controversies on MLKL, its structure, necroptosis-independent functions, expression, mutations, and its potential role as a pro- or anti-cancerous factor. Analysis of MLKL expression patterns reveals that MLKL is upregulated by type I/II interferon, conditions of inflammation, and tissue injury. Overall, MLKL may affect cancer development and metastasis through necroptosis-dependent and -independent functions.

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Fig. 1: Multiple stimuli lead to necroptosis.
Fig. 2: Structural domains of MLKL and their functions.
Fig. 3: RIPK3 and MLKL genes are differentially expressed in tissues during homeostasis.
Fig. 4: Ripk3 and Mlkl are differentially expressed in tissues during homeostasis and during perturbations.
Fig. 5: Transcriptional regulation of MLKL/Mlkl.
Fig. 6: High variation in MLKL/Mlkl expression between different types of cancer.

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Acknowledgements

SM and JB obtained a PhD fellowship from the IWT (now FWO-SB). SM, JB, NT were paid by Methusalem. Research in the Vandenabeele group is supported by Flemish grants (EOS MODEL-IDI, FWO Grant 30826052), FWO research grants (G.0E04.16N, G.0C76.18N, G.0B71.18N, G.0B96.20N), Methusalem (BOF16/MET_V/007), iBOF20/IBF/039 ATLANTIS, Foundation against Cancer (FAF-F/2016/865, F/2020/1505), CRIG and GIGG consortia, and VIB.

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SM: concept, design of figures, performing analysis, writing. JB: correction of text and figures. RR: performing analysis, figures. PV: concept, design of figures, writing and correction of text. NT: concept, design of figures, writing and correction of text

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Correspondence to Peter Vandenabeele.

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Martens, S., Bridelance, J., Roelandt, R. et al. MLKL in cancer: more than a necroptosis regulator. Cell Death Differ 28, 1757–1772 (2021). https://doi.org/10.1038/s41418-021-00785-0

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