Effects of HIF-1alpha and HIF2alpha on Growth and Metabolism of Clear-Cell Renal Cell Carcinoma 786-0 Xenografts.
In cultured clear-cell renal carcinoma (CCRCC) 786-0 cells transfected with HIF1alpha (HIF-1+), HIF-2alpha (HIF-2+), or empty vector (EV), no significant differences were observed in the growth rates in vitro, but when grown in vivo as xenografts HIF-2alpha significantly increased, and HIF-1alpha significantly decreased growth rates, compared to EV tumors. Factors associated with proliferation were increased and factors associated with cell death were decreased in HIF-2+ tumors. Metabolite profiles showed higher glucose and lower lactate and alanine levels in the HIF-2+ tumors whilst immunostaining demonstrated higher pyruvate dehydrogenase and lower pyruvate dehydrogenase kinase 1, compared to control tumors. Taken together, these results suggest that overexpression of HIF-2alpha in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage. The growth profiles observed may be mediated by adaptive changes to a more oxidative phenotype.
Biswas
Swethajit
S
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Troy
Helen
H
Leek
Russell
R
Chung
Yuen-Li
YL
Li
Ji-Liang
JL
Raval
Raju R
RR
Turley
Helen
H
Gatter
Kevin
K
Pezzella
Francesco
F
Griffiths
John R
JR
Stubbs
Marion
M
Harris
Adrian L
AL