To develop new and more efficient anti-
cancer strategies it will be important to characterize the products of
transcription factor activity essential for
tumorigenesis. One such factor is
hypoxia-inducible factor-1alpha (HIF-1alpha), a
transcription factor induced by low
oxygen conditions and found in high levels in malignant solid
tumors, but not in normal tissues or slow-growing
tumors. In fast-growing
tumors, HIF-1alpha is involved in the activation of numerous cellular processes including resistance against apoptosis, over-expression of drug efflux membrane pumps,
vascular remodeling and angiogenesis as well as
metastasis. In
cancer cells, HIF-1alpha induces over-expression and increased activity of several glycolytic
protein isoforms that differ from those found in non-malignant cells, including transporters (GLUT1, GLUT3) and
enzymes (HKI, HKII, PFK-L, ALD-A, ALD-C, PGK1, ENO-alpha, PYK-M2,
LDH-A, PFKFB-3). The enhanced
tumor glycolytic flux triggered by HIF-1alpha also involves changes in the kinetic patterns of expressed
isoforms of key glycolytic
enzymes. The HIF-1alpha induced
isoforms provide
cancer cells with reduced sensitivity to physiological inhibitors, lower affinity for products and higher catalytic capacity (Vmax(f)) in forward reactions because of marked over-expression compared to those
isoforms expressed in normal tissues. Some of the HIF1alpha-induced glycolytic
isoforms also participate in survival pathways, including transcriptional activation of H2B
histone (by
LDH-A), inhibition of apoptosis (by HKII) and promotion of cell migration (by ENO-alpha). HIF-1alpha action may also modulate mitochondrial function and oxygen consumption by inactivating the
pyruvate dehydrogenase complex in some
tumor types, or by modulating
cytochrome c oxidase subunit 4 expression to increase oxidative phosphorylation in other
cancer cell lines. In this review, the roles of HIF-1alpha and HIF1alpha-induced glycolytic
enzymes are examined and it is concluded that targeting the HIF1alpha-induced
glucose transporter and
hexokinase, important to glycolytic flux control, might provide better therapeutic targets for inhibiting
tumor growth and progression than targeting HIF1alpha itself.