Simultaneous silencing of lysophosphatidylcholine acyltransferases 1-4 by nucleic acid nanoparticles (NANPs) improves radiation response of melanoma cells

Radiation induces the generation of platelet-activating factor receptor (PAF-R) ligands, including PAF and oxidized phospholipids. Alternatively, PAF is also synthesized by the biosynthetic enzymes lysophosphatidylcholine acyltransferases (LPCATs) which are expressed by tumor cells including melanoma. The activation of PAF-R by PAF and oxidized lipids triggers a survival response protecting tumor cells from radiation-induced cell death, suggesting the involvement of the PAF/PAF-R axis in radioresistance. Here, we investigated the role of LPCATs in the melanoma cell radiotherapy response. LPCAT is a family of four enzymes, LPCAT1-4, and modular nucleic acid nanoparticles (NANPs) allowed for the simultaneous silencing of all four LPCATs. We found that the in vitro simultaneous silencing of all four LPCAT transcripts by NANPs enhanced the therapeutic effects of radiation in melanoma cells by increasing cell death, reducing long-term cell survival, and activating apoptosis. Thus, we propose that NANPs are an effective strategy for improving radiotherapy efficacy in melanomas. The membrane phospholipid phosphatidylcholine (PC) is remodeled by phospholipase A2 activity, which removes fatty acids (typically arachidonic acid) from the sn-2 position of PC, resulting in Lyso-PAF. The reverse reaction is catalyzed by LPCAT1-4 acyltransferase activity. The intermediate Lyso-PAF can be converted to PAF by LPCAT1 and LPCAT2 acetyltransferase activity and once produced, PAF is rapidly degraded to lyso-PAF by PAF acetylhydrolases (PAF-AH). With PAF playing a critical role in cancer cells' survival, we explored in the present work a modular nucleic acid nanoparticle (NANP)-based strategy for interference in PAF production by the simultaneous silencing of all four LPCAT enzymes. Our results show that in vitro silencing of LPCAT1-4 radiosensitizes melanoma cells and they encourage further investigation for the future translation of this strategy into the clinic. [Display omitted]