Targeting pyruvate dehydrogenase kinase signaling in the development of effective cancer therapy

Pyruvate is irreversibly decarboxylated to acetyl coenzyme A by mitochondrial pyruvate dehydrogenase complex (PDC). Decarboxylation of pyruvate is considered a crucial step in cell metabolism and energetics. The cancer cells prefer aerobic glycolysis rather than mitochondrial oxidation of pyruvate....

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Published in:Biochimica et biophysica acta. Reviews on cancer 2021-08, Vol.1876 (1), p.188568-188568, Article 188568
Main Authors: Anwar, Saleha, Shamsi, Anas, Mohammad, Taj, Islam, Asimul, Hassan, Md. Imtaiyaz
Format: Article
Language:English
Subjects:
Cancer signaling
Cancer therapeutics
Drug development
Drug targets
Kinase inhibitors
OXPHOS
Pyruvate dehydrogenase kinase
Warburg effect
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Summary:Pyruvate is irreversibly decarboxylated to acetyl coenzyme A by mitochondrial pyruvate dehydrogenase complex (PDC). Decarboxylation of pyruvate is considered a crucial step in cell metabolism and energetics. The cancer cells prefer aerobic glycolysis rather than mitochondrial oxidation of pyruvate. This attribute of cancer cells allows them to sustain under indefinite proliferation and growth. Pyruvate dehydrogenase kinases (PDKs) play critical roles in many diseases because they regulate PDC activity. Recent findings suggest an altered metabolism of cancer cells is associated with impaired mitochondrial function due to PDC inhibition. PDKs inhibit the PDC activity via phosphorylation of the E1a subunit and subsequently cause a glycolytic shift. Thus, inhibition of PDK is an attractive strategy in anticancer therapy. This review highlights that PDC/PDK axis could be implicated in cancer's therapeutic management by developing potential small-molecule PDK inhibitors. In recent years, a dramatic increase in the targeting of the PDC/PDK axis for cancer treatment gained an attention from the scientific community. We further discuss breakthrough findings in the PDC-PDK axis. In addition, structural features, functional significance, mechanism of activation, involvement in various human pathologies, and expression of different forms of PDKs (PDK1-4) in different types of cancers are discussed in detail. We further emphasized the gene expression profiling of PDKs in cancer patients to prognosis and therapeutic manifestations. Additionally, inhibition of the PDK/PDC axis by small molecule inhibitors and natural compounds at different clinical evaluation stages has also been discussed comprehensively.
ISSN:0304-419X
1879-2561
DOI:10.1016/j.bbcan.2021.188568