Hepatocyte growth factor/
scatter factor (HGF) is a multifunctional
growth factor that is linked to the initiation and/or progression of numerous
malignancies. HGF also alters
cancer cell responses to
DNA damaging
cytotoxic agents. Many cell responses to Met activation require alterations in metabolic activity but how the metabolic machinery responds to Met activation remains poorly defined. Treating human
glioblastoma cells with HGF followed by the
topoisomerase inhibitor camptothecin was found to increase the activity per cell of the mitochondrial respiratory chain
enzyme succinate-tetrazolium
reductase (>80% increase, p < 0.05) and the tricarboxylic acid cycle
enzyme succinate dehydrogenase (>25% increase, p < 0.05). Treatment with either HGF or
camptothecin alone had no effect on
enzyme activity. The mitochondrial enzymatic response to HGF was dose- and time-dependent with the maximum increase occurring in cells pre-treated with 30 ng/ml HGF for 48h prior to
camptothecin exposure. This enzymatic response was associated with a concurrent increase in mitochondrial mass of comparable magnitude (approximately 56%, p < 0.05) as measured by fluorescent mitochondrial staining and flow cytometry. The mitochondrial mass response to HGF was prevented by the MAP-
kinase pathway inhibitor
PD98059 and was unaffected by the
phosphatidylinositol 3-kinase inhibitors
LY294002 and
wortmannin. These findings suggest that HGF influences cell responses to chemotherapeutic stress, in part, by altering mitochondrial functions through a MAP-
kinase dependent increase in mitochondrial mass.