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

Abstract

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.

Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer

“…In fast-growing tumors, HIF-1· plays crucial roles in the activation of numerous cellular processes, including cell immortalization, cell growth and survival, invasion/metastasis, angiogenesis, resistance to chemotherapy, and overexpression of drug efflux membrane pumps (28,29). A recent report has shown that artemisinin induces DOX resistance by decreasing DOX accumulation and cytotoxicity in human colon cancer cells through the activation of HIF-1· and P-gp overexpression (30).…”

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

“…This indicates that HIF-3α also possesses transcriptional activity. All the hHIF-3α variants were demonstrated to be able to bind to HIF-β and overexpression of certain HIF-3α variants, together with HIF-β, induces the mRNA expression levels of several HIF-1 and HIF-2 target genes, including EPO (56,57), ANGPTL4 (58,59) and GLUT1 (60,61). However, the overexpression of HIF-3α variants reveals no significant stimulation of the expression of HRE-driven reporter genes (62), suggesting that the target genes induced by HIF-3α variants may contain specific response elements, which are not canonical HREs (31,62).…”

Tumor cell metabolism

“…These include glucose transporters (GLUT1, GLUT3), glycolytic enzymes (HKI, HKII, PFK-1, ALDO-A, ALDO-C, PGK1, ENO-a, PK-M2, PFKFB-3) and enzymes related to lactate production and lactate/proton extrusion (LDH-A, MCT4). 33,34 Hypoxia also induces the expression of the pyruvate dehydrogenase kinases (PDK1 and PDK3 isoforms), 26,35 which have different activities and specificities for the phosphorylation and inactivation of the three isoforms of pyruvate dehydrogenases (PDHA1, PDHA2 and PDHB), 36,37 which transform pyruvate into acetyl-CoA (Fig. 2).…”