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

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 activation^3,4; 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.