Epidermal growth factor (EGF) augments the invasive potential of human glioblastoma multiforme cells via the activation of collaborative EGFR/ROS-dependent signaling
Epidermal growth factor (EGF) augments the invasive potential of human glioblastoma multiforme cells via the activation of collaborative EGFR/ROS-dependent signaling
Epidermal growth factor (EGF) augments the invasive potential of human glioblastoma multiforme cells via the activation of collaborative EGFR/ROS-dependent signaling
author:
Pudełe Maciej, Król Kamila, Catapano Jessica , Wróbel Tomasz , Czyż Jarosław , Ryszawy Damian
Abnormal secretion of epidermal growth factor (EGF) by non-neuronal cells (e.g., gliomaassociated microglia) establishes a feedback loop between glioblastoma multiforme (GBM) invasion
and a functional disruption of brain tissue. Considering the postulated significance of this vicious circle
for GBM progression, we scrutinized mechanisms of EGF-dependent pro-invasive signaling in terms
of its interrelations with energy metabolism and reactive oxygen species (ROS) production. The effects
of EGF on the invasiveness of human glioblastoma T98G cells were estimated using time-lapse
video microscopy, immunocytochemistry, cell cycle assay, immunoblot analyses, and Transwell®
assay. These techniques were followed by quantification of the effect of EGFR (Epidermal Growth
Factor Receptor) and ROS inhibitors on the EGF-induced T98G invasiveness and intracellular
ROS, ATP, and lactate levels and mitochondrial metabolism. The EGF remarkably augmented
the proliferation and motility of the T98G cells. Responses of these cells were accompanied by
cellular rear–front polarization, translocation of vinculin to the leading lamellae, and increased
promptness of penetration of micropore barriers. Erlotinib (the EGFR inhibitor) significantly
attenuated the EGF-induced T98G invasiveness and metabolic reprogramming of the T98G cells,
otherwise illustrated by the increased mitochondrial activity, glycolysis, and ROS production in
the EGF-treated cells. In turn, ROS inhibition by N-acetyl-L-cysteine (NAC) had no effect on
T98G morphology, but considerably attenuated EGF-induced cell motility. Our data confirmed the
EGFR/ROS-dependent pro-neoplastic and pro-invasive activity of EGF in human GBM. These EGF
effects may depend on metabolic reprogramming of GBM cells and are executed by alternative
ROS-dependent/-independent pathways. The EGF may thus preserve bioenergetic homeostasis of
GBM cells in hypoxic regions of brain tissue.