Hypoxia‐induced proliferation of HeLa cells depends on epidermal growth factor receptor‐mediated arginase II induction

Abstract

Solid tumors can often be hypoxic in regions, and cancer cells can respond to hypoxia with an increase in proliferation and a decrease in apoptosis, leading to a net increase in viable cell numbers. We have recently found that in an osteosarcoma cell line, hypoxia‐induced proliferation depends on arginase II induction. Epidermal growth factor receptor (EGFR) has been shown to mediate the hypoxia‐induced cellular proliferation in some cancer cell lines. We hypothesized that hypoxia‐induced proliferation of HeLa cells would depend on arginase II induction and that this induction of arginase II would occur through EGFR activation. Exposure of HeLa cells to hypoxia resulted in an upregulation of arginase II mRNA and protein levels, with no effect on arginase I expression. Hypoxia also resulted in significantly greater viable cell numbers than did normoxia. The hypoxia‐induced increase in viable cell numbers was prevented by either a small molecule inhibitor of arginase or siRNA targeting arginase II. Overexpression of arginase II resulted in an increase in viable cell numbers both in normoxia and hypoxia. Hypoxia caused a substantial induction of both epidermal growth factor (EGF) and EGFR. Preventing hypoxia‐induced EGFR expression using siRNA abolished hypoxia‐induced arginase II expression and the increase in viable cell numbers. Treatment with EGF in normoxia not only induced arginase II expression but also resulted in an increase in viable cell numbers. Blocking EGF interactions with EGFR using either an EGF neutralizing antibody or an EGFR antibody prevented the hypoxia‐induced increase in viable cell numbers. These results demonstrate an EGF/EGFR/arginase II pathway that is necessary for hypoxic proliferation in HeLa cells.

Hypoxic-induction of arginase II requires EGF-mediated EGFR activation in human pulmonary microvascular endothelial cells

“…These finding are consistent with our previous studies (Setty et al. ) in HeLa cells and supports the concept of a hypoxia responsive EGF‐EGFR pathway in endothelial cells leading to arginase II expression. It has been described that endothelial release of various growth factors, including EGF, can activate epidermal cells in the lung to promote lung development.…”

“…We have previously shown that exposing HeLa cells to 1% oxygen resulted in a ~20‐fold increase in EGF mRNA and a substantial increase in pEGFR protein levels (Setty et al. ). Our results demonstrate that hypoxia also leads to a substantial increase in EGF expression and subsequent EGFR activation in hPMVEC.…”

Ammonia generation by tryptophan synthase drives a key genetic difference between genital and ocular Chlamydia trachomatis isolates

“…conditions (4% O 2 ) (67-69). Our findings correspond to observations made by others with HeLa cells, in that oxidative radicals have been observed at significant levels during normoxic culture (70); in contrast, hypoxia relieves oxidative stress and increases the viability of HeLa cells (71). In this regard, physiological oxygen tensions in the majority of human tissues range from 0 to 5% O 2 ; for example, vaginal oxygen tension is typically 1-2% O 2 , rising briefly to 5% O 2 during sexual stimulation (72); a similar range has been observed for cervical and uterine oxygen tension (73).…”

Ataxin-1 is involved in tumorigenesis of cervical cancer cells via the EGFR-RAS–MAPK signaling pathway

“…To identify the molecular mechanism underlying cell growth in cervical cancer promoted by ATXN1, we analyzed the relevant regulatory signaling pathways. EGF induces cell growth in human cancer cells [ 19 ] and activates the Akt and ERK signaling pathways [ 31 , 32 ]. Considering this, we hypothesized that ATXN1 is involved in EGF-mediated cancer growth.…”

“…EGF is a 6-kDa polypeptide that elicits a number of biological responses, including profound alterations in cellular growth and differentiation, in a variety of normal and tumoral cell types [ 18 , 19 ]. EGF induces cell proliferation by binding to the prototype transmembrane tyrosine kinase receptors 1 and 2, resulting in the phosphorylation of several protein components.…”