The Implications of PDK1-4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

Abstract

A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis-known as the Warburg effect-is characteristic for many cancers. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. The main regulators of this metabolic shift are the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK is known to be overexpressed in several cancers and is associated with bad prognosis and therapy resistance. Whereas the expression of PDK1-3 is tissue specific, PDK4 expression is dependent on the energetic state of the whole organism. In contrast to other PDK isoforms, not only oncogenic, but also tumor suppressive functions of PDK4 have been reported. In tumors that profit from high OXPHOS and high de novo fatty acid synthesis, PDK4 can have a protective effect. This is the case for prostate cancer, the most common cancer in men, and makes PDK4 an interesting therapeutic target. While most work is focused on PDK in tumors characterized by high glycolytic activity, little research is devoted to those cases where PDK4 acts protective and is therefore highly needed.

Keywords: Warburg effect; aerobic glycolysis; cancer metabolism; oxidative phosphorylation; prostate cancer; pyruvate dehydrogenase kinase; therapy resistance; tricarboxylic acid cycle.

Figure 1

Simplified scheme of the mitochondrion with TCA cycle and the intersecting anaplerotic and cataplerotic reactions, OXPHOS complexes I–IV, and ATP synthase (complex V). In the mitochondrial matrix the PDC catalyzes the irreversible conversion of pyruvate, NAD+ and CoA into acetyl-CoA, NADH and CO₂. PDK inactivate the PDC by phosphorylating its E1α subunit, which hinders the entrance of acetyl-CoA into the TCA cycle. The PDC is reactivated upon dephosphorylation by PDP. Adapted from (5). Inspiration (4, 6).

Figure 2

Energy metabolism of the prostate. (A) Healthy prostate cells accumulate high amounts of zinc, which inhibit the enzyme m-aconitase and thereby truncate the TCA cycle. (B) Prostate tumor cells show lower levels of zinc, whereby the enzyme aconitase remains active and citrate can be metabolized via the TCA cycle and OXPHOS. Taken from (5), inspired by (78).