ABSTRACT: Background Few studies have reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein suppresses 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). Methods To evaluate its anticancer activity, we performed RNA sequencing, colony formation, immunofluorescence, cell viability, migration, FACS, western blotting, 3D spheroid, molecular docking, siRNA,qRT-PCR, and apoptosis assays. Results 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 suppressed migration, spheroid growth, and sub-G1 arrest. RNA-Seq revealed distinct expression profiles between control and SP-treated cells, identifying two differentially expressed lncRNAs: MEG3 was upregulated, while BCYRN1 was downregulated. Knockdown of BCYRN1 or overexpression of MEG3 reproduced the spike protein–induced antiproliferative and pro-apoptotic effects, including enhanced cleaved caspase-3 expression. Docking analysis suggested potential binding of spike protein to these lncRNAs. To determine whether spike protein affects their stability, transcription was inhibited using actinomycin D (ActD). Spike protein attenuated the ActD-induced decrease of MEG3, indicating enhanced stability, whereas it accelerated BCYRN1 reduction. Conclusion Collectively, these findings demonstrate that SARS-CoV-2 spike protein exerts antitumor activity in A549 lung cancer cells by differentially regulating the stability of lncRNAs MEG3 and BCYRN1.
