Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma

Abstract

Pyruvate dehydrogenase (PDH) catalyzes the conversion 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 hypoxic conditions, conversion of pyruvate to lactate occurs, a reaction catalyzed by lactate dehydrogenase 5 (LDH5). In cancer cells, however pyruvate is transformed to lactate occurs, regardless of the presence of oxygen (aerobic glycolysis/Warburg effect). Although, hypoxic intratumoral conditions account for HIF1alpha stabilization and induction of anaerobic metabolism, recent data suggest that high pyruvate concentrations also result in HIF1alpha 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 HIF1alpha stabilization and "aerobic glycolysis." However, about half of PDH-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.

Figure 1

Expression patterns of PDH and PDK in normal lung and lung cancer. (a) Strong cytoplasmic expression of PDH in normal bronchi (thick arrows) and adjacent stroma fibroblasts (thin arrows). (b) Intense PDH expression in the alveolar tissue (thick arrows). (c) Lack of PDH expression in a squamous cell lung carcinoma (thin arrows) adjacent to PDH-positive alveolar tissue (thick arrows). (d) Focal PDH expression in cancer cells (black arrows). (e) Lack of PDH expression in squamous cell lung cancer (thin arrows) in a background of tumor-supporting stroma exhibiting a strong PDH reactivity (thick arrows). Strong expression of PDK in cancer cells (thin arrows) of a squamous cell carcinoma (f) and adenocarcinoma (g). Note the repression of PDK in the tumor-supporting stroma (thick arrows).

Figure 2

Kaplan-Meier overall survival curves according to PDH expression, stratified for HIF1α (a) and LDH5 expression (b) (n = 42). Note that cases with contemporaneous defective metabolism in both aerobic (low PDH expression) and anaerobic (low HIF1α or low LDH5) directions had a particularly favorable outcome.