PDHK Enzyme Identified as a Promising Therapeutic Target for Treating Cancer

 A new study suggests that looking at the accelerated rate at which cancer cells metabolize sugar may provide valuable insight into the development of effective targets for drug therapy.

The uncontrolled cell growth characteristic of cancer cells is due to abnormalities of the metabolism in those cells—specifically, how these cells use sugar. Looking at the enzyme and processes surrounding this sugar breakdown will be valuable in developing drugs to stop or slow the growth of cancer cells, according to a study by the Emory University Winship Cancer Institute.

The study is based on the principles of the Warburg Effect, which deals with the metabolic requirements for cell proliferation and compares the unique metabolic property of cancer cells with those of normal differentiated cells. Cancer cells prefer to use the anaerobic method of glycolysis to break down sugars and generate adenosine triphosphate (ATP), as opposed to the aerobic process of oxidative phosphorylation to create energy. Cancer cells have a metabolic advantage when they use glycolysis for cell energy, even though it is considered a less efficient method, because they do not produce as many molecules of ATP as does oxidative phosphorylation. As a result of glycolysis, cancer cells are able to generate ATP more quickly, which can lead to an increase in cell growth rate. Additionally, glycolysis produces glycolytic intermediates, which serve as precursors for the biosynthesis of the molecules that are the building blocks of cancer proliferation.

The Emory study specifically looked at how cancer cells utilize the process of glycolysis and how glycolysis starts in cancer cells. A cell is directed to produce energy (ATP) through glycolysis when the mitochondria is functionally inhibited, and these directions come from an enzyme. In the case of cancer cells, the enzyme that flips the metabolic switch from aerobic respiration to glycolysis was found to be pyruvate dehydrogenase kinase (PDHK).

Co-corresponding author Jing Chen, PhD, associate professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute and colleagues found that tyrosine kinases activate PDHK. PDHK affects cancer cell metabolism by shutting off cellular respiration in the mitochondria. As a result, glycolysis ensues, and energy for cell growth is acquired at a much faster speed.

Researchers found that introducing a form of PDHK that is resistant to tyrosine kinases into human cancer cells caused the cells to proliferate more slowly in the tumors of mice. This indicates that drugs that inactivate PDHK in cancer cells may be useful to slow uncontrolled cell growth.

There are already clinical trials in process studying drugs that inhibit PDHK, most of them with a focus on using the experimental drug dichloroacetate for the treatment of cancer. Dr. Chen, along with Haian Fu, PhD, professor of pharmacology and director of the Emory Chemical Biology Discovery Center, are developing their own PDHK inhibitor in the compound screening chemical center at Emory. They hope to develop a more specific and potent inhibitor to use as an anti-cancer agent. Their proposed inhibitor would inhibit PDHK by expressing a less active form of the enzyme in cancer cells, called PDHK-1.

Researchers were also surprised to discover the true location of tyrosine kinases in the cell—they work within the mitochondria to influence cell growth, as opposed to functioning at the cell membrane as previously thought. It was also previously assumed that cancer cells used glycolysis only because their mitochondria were irreparably damaged and they could not metabolize sugars within this organelle.

Identification of the metabolic processes of cells and the enzymes affecting this function has important implications for the development of drugs to fight cancer.