Kinase Expression in Non Small Cell Lung Cancer

Pyruvate dehydrogenase (PDH) catalyzes the conver-sion of pyruvate to acetyl-coenzyme A, which enters into the Krebs cycle, providing adenosine triphosphate (ATP) to the cell. PDH activity is under the control of pyruvate dehydrogenase kinases (PDKs). Under hyp-oxic conditions, conversion of pyruvate to lactate occurs, a reaction catalyzed by lactate dehydrogenase 5 (LDH5). In cancer cells, however, pyruvate is trans-formed to lactate occurs, regardless of the presence of oxygen (aerobic glycolysis/Warburg effect). Although hypoxic intratumoral conditions account for HIF1A stabilization and induction of anaerobic metabolism, recent data suggest that high pyruvate concentrations also result in HIF1A stabilization independently of hypoxia. In the present immunohistochemical study, we provide evidence that the PDH/PDK pathway is repressed in 73 % of non small cell lung carcinomas, which may be a key reason for HIF1A stabilization and ‘‘aerobic glycolysis.’ ’ However, about half of PDH-deficient carcinomas are not able to switch on the HIF pathway, and patients harboring these tumors have an excellent postoperative outcome. A small subgroup of clinically aggressive tumors maintains a coherent PDH and HIF/LDH5 expression. In contrast to cancer cells, fibroblasts in the tumor-supporting stroma exhibit an intense PDH but reduced PDK1 expression favoring maximum PDH activity. This means that stroma may use lactic acid produced by tumor cells, preventing the creation of an intolerable intratumoral acidic environment at the same time