Expression of ACE2, TMPRSS2, and GRP78 and their association with SARS-CoV-2 pseudovirus susceptibility in non-small cell lung cancer cells

Abstract Background Non-small cell lung cancer (NSCLC) patients often experience worse complications from coronavirus disease 2019 (COVID-19). The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection starts as the viral spike (S) protein attaches to angiotensin-converting enzyme 2 (ACE2), requiring transmembrane protease serine 2 (TMPRSS2) as a co-receptor. Additionally, glucose-regulated protein 78 (GRP78) may serve as an alternative receptor in certain conditions. However, studies on the expression of ACE2, TMPRSS2, and GRP78 in NSCLC and their association with SARS-CoV-2 susceptibility remain limited. This study investigates whether NSCLC receptor expression increases SARS-CoV-2 infection risk. Methods This study evaluated protein and gene expression of ACE2, TMPRSS2, and GRP78 in NSCLC cell lines (Calu-3, A549, H460) versus normal lung fibroblasts (MRC5) using flow cytometry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and assessed whether their expression increases SARS-CoV-2 infection risk via SARS-CoV-2 pseudovirus transduction. Results Results showed higher ACE2 and TMPRSS2 expression and greater susceptibility to SARS-CoV-2 pseudovirus in Calu-3, whereas A549 and H460 showed higher TMPRSS2 protein levels but unchanged ACE2 expression and viral susceptibility. No significant association was also observed between GRP78 levels and SARS-CoV-2 pseudovirus infection severity in NSCLC cells. Conclusion These findings suggest that ACE2 and TMPRSS2 levels are positively correlated with SARS-CoV-2 pseudovirus infectivity. Moreover, elevated TMPRSS2 expression alone is insufficient to enhance susceptibility unless accompanied by increased ACE2 expression. This study highlights potential therapeutic targets for mitigating SARS-CoV-2 infection risk in NSCLC patients by modulating receptor expression.