Epinephrine augments the phosphorylation of EGFR and promote the DNA synthesis and migration of cervical cancer cells.

Abstract

Though a correlation exists between carcinogenesis and epinephrine signaling, the ability of epinephrine in regulating epidermal growth factor (EGF) actions remains largely unknown and necessitates investigation in cervical cancer (CC) cells. The present study aims to understand the role of epinephrine, a stress-induced cytokine on EGF actions in human papilloma virus (HPV)-positive SiHa, ME180 and HPV-negative C33A cells. De-identified database and molecular docking were used to identify the relationship between beta-adrenergic receptor 2 (ADRB2) and EGF receptor (EGFR). Cell viability, mitochondrial labeling, reactive oxygen species (ROS) production, evaluation of ADRB2 and superoxide dismutase-2 (SOD-2) mRNA abundance, SOD-1/2 enzymatic activities, migration assay, gelatin zymography and protein expression analysis of epithelial-mesenchymal transition (EMT) markers were performed to validate the regulatory role of epinephrine and EGF. A significant up-regulation of ADRB2 in HPV-16-positive individuals and binding between epinephrine and EGFR is noted computationally. A reduced survival in high ADRB2 along with the significant reduction in CC survival in Asian population is also observed. Epinephrine augmented the phosphorylation of EGFR and EGF-induced cell viability, ROS production and DNA synthesis. A positive correlation between SOD-2 and ADRB2 was corroborated with the increased ADRB2 and SOD-2 mRNA transcripts. An increase in MMP-2 activity and EMT markers by EGF and epinephrine potentiated the CC cells toward enhanced migration. This study also opens up several new avenues and warrants substantial in vivo studies to support this contention for the inclusion of beta-blockers as adjuvant for EGFR-driven cancers.