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Cancer therapy-induced PAFR ligand expression: any role for caspase activity?

Nature Reviews Cancer volume 17, page 253 (2017)Cite this article

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Our recent Opinion article discussed the oncogenic effects of engaging apoptosis and their impact on cancer (Nat. Rev. Cancer 16, 539–548; 2016)1. We would like to thank Roger Chammas, Luciana Nogueira de Sousa Andrade and Sonia Jancar for their correspondence on our article (Nat. Rev. Cancer (2017) doi:10.1038/nrc.2017.15)2. Caspase protease activity is essential for apoptotic cell death. Among hundreds of diverse substrates, caspases cleave Ca2+-independent phospholipase A2 (iPLA2) leading to its activation3,4; active iPLA2 cleaves phosphatidylcholine to give arachidonic acid and lysophosphatidylcholine (LPC). Through cyclooxygenase enzymatic activity, arachidonic acid can be converted into prostaglandin E2 (PGE2) — a prostanoid that has tumour-promoting properties. Consequently, this provides one means whereby caspase-dependent apoptosis could promote cancer5.

Chammas and colleagues2 highlight oncogenic functions for platelet-activating factor receptor (PAFR) signalling; this is mediated following receptor binding to platelet-activating factor (PAF) and related PAFR ligands. Various cell-killing anticancer therapies, notably radiation, are strong inducers of PAF and PAFR ligands. As the authors discuss, during apoptosis PAF might be produced from LPC (generated by caspase-activated iPLA2) through the action of lysophosphatidylcholine acyltransferases (LPCATs). Although we find this possibility interesting, it is unknown whether apoptotic cells generate PAF in a caspase-dependent manner. Indeed, radiation and chemotherapies induce PAF and PAFR ligands in a non-enzymatic manner (dependent on phospholipid oxidation)6,7, arguing against a major role for caspase-dependent generation of PAF. Given this, the rationale for directly targeting PAFR signalling in cancer therapy seems more compelling than that for inhibiting putative, caspase-dependent PAF generation.

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References

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  1. Gabriel Ichim and Stephen Tait are at the Cancer Research UK Beatson Institute and the Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.,

    Gabriel Ichim & Stephen W. G. Tait

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  1. Gabriel Ichim
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Correspondence to Stephen W. G. Tait.

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Ichim, G., Tait, S. Cancer therapy-induced PAFR ligand expression: any role for caspase activity?. Nat Rev Cancer 17, 253 (2017). https://doi.org/10.1038/nrc.2017.16

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