Title:Inhibition of Pyruvate Dehydrogenase Kinase as a Therapeutic Strategy against Cancer
Volume: 18
Issue: 6
Author(s): Swatishree Sradhanjali and Mamatha M. Reddy*
Affiliation:
- The Operation Eyesight Universal Institute for Eye Cancer, L V Prasad Eye Institute, Bhubaneswar,India
Keywords:
Pyruvate dehydrogenase kinase (PDK), cancer, glucose metabolism, PDK regulation, cancer stemness, therapy
related resistance, PDK inhibition.
Abstract: Cancer cells alter their metabolism to support the uninterrupted supply of biosynthetic molecules
required for continuous proliferation. Glucose metabolism is frequently reprogrammed in several
tumors in addition to fatty acid, amino acid and glutamine metabolism. Pyruvate Dehydrogenase Kinase
(PDK) is a gatekeeper enzyme involved in altered glucose metabolism in tumors. There are four isoforms
of PDK (1 to 4) in humans. PDK phosphorylates E1α subunit of pyruvate dehydrogenase complex
(PDC) and inactivates it. PDC decarboxylates pyruvate to acetyl CoA, which is further metabolized
in mitochondria. Overexpression of PDK was observed in several tumors and is frequently associated
with chemotherapy related drug resistance, invasion and metastasis. Elevated expression of PDK leads
to a shift in glucose metabolism towards glycolysis instead of oxidative phosphorylation. This review
summarizes recent literature related to the role of PDKs in cancer and their inhibition as a strategy. In
particular, we discuss the role of PDK in tumor progression, metabolic reprogramming in stem cells, and
their regulation by miRNAs and lncRNAs, oncogenes and tumor suppressors. Further, we review strategies
aimed at targeting PDK to halt tumor growth and progression.
