Journal
MOLECULAR CANCER THERAPEUTICS
Volume 18, Issue 10, Pages 1673-1681Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-19-0079
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Funding
- National Cancer Institute Cancer Center Support Grant [P30 CA168524]
- Leo and Anne Albert Charitable Trust
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Cancer cells use alterations of normal metabolic processes to sustain proliferation indefinitely. Transcriptional and post-transcriptional control of the pyruvate dehydrogenase kinase (PDK) family is one way in which cancer cells alter normal pymvate metabolism to fuel proliferation. PDKs can phosphorylate and inactivate the pyruvate dehydrogenase complex (PDHC), which blocks oxidative metabolism of pyruvate by the mitochondria. This process is thought to enhance cancer cell growth by promoting anabolic pathways. Inhibition of PDKs induces cell death through increased PDH activity and subsequent increases in ROS production. The use of PDK inhibitors has seen widespread success as a potential therapeutic in laboratory models of multiple cancers; however, gaps still exist in our understanding of the biology of PDK regulation and function, especially in the context of individual PDKs. Efforts are currently underway to generate PDK-specific inhibitors and delineate the roles of individual PDK isozymes in specific cancers. The goal of this review is to understand the regulation of the PDK isozyme family, their role in cancer proliferation, and how to target this pathway therapeutically to specifically and effectively reduce cancer growth.
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