HIF-1 Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms

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.