The S1 subunit of spike protein and its receptor-binding domain increased the expression of the anti-apoptotic protein survivin

The UAE and Qatar research group used lung cancer cell line (A549 cells) expressing the angiotensin-converting enzyme 2 (ACE2) receptors to investigate the activation of the epidermal growth factor receptor (EGFR) by the spike 1 S protein (S1) and its receptor-binding domain (RBD). The results showed that the spike 1 S protein and its receptor-binding domain increased the expression and the activation of the anti-apoptotic protein, survivin. Survivin belongs to the inhibitor of apoptosis family and is considered a the key marker for the activation of the survival pathway in cancer cells.

A large body of evidence from in vitro studies strongly supports the thesis that the angiotensin-converting enzyme 2 (ACE2) receptor is necessary for SARS-CoV-2 entry. However, it was suggested that other factors and/or alternative cell surface receptors may also be implicated in the entry of SARS-CoV-2. The assumption was made that SARSCoV-2 could also use the epidermal growth factor receptor (EGFR) expressed on the epithelial lung cells as the receptor/co-receptor target for its entry.

About the study

Protein expression and phosphorylation were examined upon cell treatment with either recombinant full S1 (2.5 μg/ml) or its RBD (5 μg/ml) for 5, 15, 30, and 60 min.

The results demonstrated for the first time the possible hijacking of EGFR and its related downstream signaling pathways by SARS-CoV-2 Spike 1 protein and its RBD in lung cancer cells. In addition, S1 and its RBD elicited the activation of the survival pathway in A549 cells. Both S1 and RBD increased the expression and the activation of the anti-apoptotic protein, survivin, in a time-dependent manner with a maximal response at 30 and 60 minutes. Survivin activation by both S1- and RBD in A549 cells was significantly diminished (~ by 2 to 5 fold) by the EGFR antagonist, AG1478, demonstrating the involvement of EGFR/AKT axis in the upregulation of survivin.

Survivin belongs to the inhibitor of apoptosis family and is considered a the key marker for the activation of the survival pathway in cancer cells. The authors noted that expression and the activation of the anti-apoptotic protein survivin may be a solid molecular and cellular rationale to explain the severity of SARS-CoV-2 infection in cancer patients as reported by several groups.

This article was published in the scientific journal Vaccines. Palakkott, A.R. et al. The SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling. Vaccines 2023, 11, 768.  https://doi.org/10.3390/vaccines11040768