Hypoxia-induced proliferation of HeLa cells depends on epidermal growth factor receptor-mediated arginase II induction.
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.
Pulmonary Hypertension Group, Center for Perinatal Research The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
Bhuvana A
BA
Setty
Pulmonary Hypertension Group, Center for Perinatal Research The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
Natasha
N
Pillay Smiley
Pulmonary Hypertension Group, Center for Perinatal Research The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
Caitlyn M
CM
Pool
Pulmonary Hypertension Group, Center for Perinatal Research The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
Yi
Y
Jin
Pulmonary Hypertension Group, Center for Perinatal Research The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
Yusen
Y
Liu
Pulmonary Hypertension Group, Center for Perinatal Research The Research Institute at Nationwide Children's Hospital, Columbus, Ohio Leif.Nelin@nationwidechildrens.org.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
Leif D
LD
Nelin
D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
D034741:RNA, Small Interfering; D066246:ErbB Receptors; C477631:ARG2 protein, human; D001119:Arginase
Cancer; cell signaling; epidermal growth factor