SARS-CoV-2 spike protein exerts an anti-cancer effect in A549 cells in association with MEG3 and BCYRN1 regulation

Few studies have reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein may suppress cancer cell growth. Here, we investigated the effect of the SARS-CoV-2 spike protein in A549 lung cancer cells using recombinant spike protein (SP), spike protein transfection (SPT), and pseudo-SARS-CoV-2 virus (PSV). To evaluate its anticancer effects and associated molecular changes, we performed RNA sequencing, colony formation, immunofluorescence, cell viability, migration, FACS, western blotting, 3D spheroid, molecular docking, siRNA knockdown, qRT-PCR, apoptosis assays, and computational interaction analyses. Spike protein significantly inhibited the long-term growth of A549 cells. Among the delivery methods, PSV showed the most potent anticancer effect, followed by SPT and SP, as evidenced by reduced migration, spheroid growth, and increased sub-G1 arrest. RNA-Seq identified two differentially expressed lncRNAs, with MEG3 upregulated and BCYRN1 downregulated following spike-related treatment. Functional experiments showed that BCYRN1 knockdown or MEG3 overexpression reproduced key spike protein-induced antiproliferative and pro-apoptotic effects, including increased cleaved caspase-3 expression. Computational analyses suggested possible interactions between the Spike protein and these lncRNAs. In addition, actinomycin D (ActD) chase experiments indicated altered transcript dynamics of MEG3 and BCYRN1 under spike-related conditions. Collectively, these findings suggest that SARS-CoV-2 spike protein exerts antitumor activity in A549 cells and may contribute to the regulation of MEG3 and BCYRN1. Further studies, including formal rescue and biochemical interaction assay, will be required to establish causality and direct molecular mechanisms.