In early studies on energy metabolism of tumor cells, it was proposed that the enhanced glycolysis was induced by a decreased oxidative phosphorylation. Since then it has been indiscriminately applied to all types of tumor cells that the ATP supply is mainly or only provided by glycolysis, without an appropriate experimental evaluation. In this review, the different genetic and biochemical mechanisms by which tumor cells achieve an enhanced glycolytic flux are analyzed. Furthermore, the proposed mechanisms that arguably lead to a decreased oxidative phosphorylation in tumor cells are discussed. As the O₂ concentration in hypoxic regions of tumors seems not to be limiting for the functioning of oxidative phosphorylation, this pathway is re‐evaluated regarding oxidizable substrate utilization and its contribution to ATP supply versus glycolysis. In the tumor cell lines where the oxidative metabolism prevails over the glycolytic metabolism for ATP supply, the flux control distribution of both pathways is described. The effect of glycolytic and mitochondrial drugs on tumor energy metabolism and cellular proliferation is described and discussed. Similarly, the energy metabolic changes associated with inherent and acquired resistance to radiotherapy and chemotherapy of tumor cells, and those determined by positron emission tomography, are revised. It is proposed that energy metabolism may be an alternative therapeutic target for both hypoxic (glycolytic) and oxidative tumors.

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-1α (HIF-1α), 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-1α 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-1α 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-α, PYK-M2, LDH-A, PFKFB-3). The enhanced tumor glycolytic flux triggered by HIF-1α also involves changes in the kinetic patterns of expressed isoforms of key glycolytic enzymes. The HIF-1α induced isoforms provide cancer cells with reduced sensitivity to physiological inhibitors, lower affinity for products and higher catalytic capacity (Vmaxf) in forward reactions because of marked over-expression compared to those isoforms expressed in normal tissues. Some of the HIF1α-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-α). HIF-1α 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-1α and HIF1α- induced glycolytic enzymes are examined and it is concluded that targeting the HIF1α-induced glucose transporter and hexokinase, important to glycolytic flux control, might provide better therapeutic targets for inhibiting tumor growth and progression than targeting HIF1α itself.

Mitochondria become targets for autophagic degradation after nutrient deprivation, a process also termed mitophagy. In this study, we used LysoTracker Red (LTR) and MitoTracker Green to characteriz...