Inhibition of Pyruvate Dehydrogenase Kinase as a Therapeutic Strategy against Cancer

Author(s): Swatishree Sradhanjali, Mamatha M. Reddy*.

Journal Name: Current Topics in Medicinal Chemistry

Volume 18 , Issue 6 , 2018

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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.

Keywords: Pyruvate dehydrogenase kinase (PDK), cancer, glucose metabolism, PDK regulation, cancer stemness, therapy related resistance, PDK inhibition.

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Article Details

VOLUME: 18
ISSUE: 6
Year: 2018
Page: [444 - 453]
Pages: 10
DOI: 10.2174/1568026618666180523105756
Price: $58

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