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Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti-cancer effect
Zhang, Wen; Zhang, Shao-Lin; Hu, Xiaohui; Tam, Kin Yip
Conference Name5th Meeting of the International-Association-of-Physical-Chemists (IAPC)
Conference Date2016-8-23-26
Conference PlaceZhuhai, PEOPLES R CHINA
Publication PlacePO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS

Phenyl butyrate (PB) has been proved to decrease pyruvate dehydrogenase (PDH) phosphorylation level and increase PDH activity by inhibiting pyruvate dehydrogenase kinase 1 (PDK1) in fibroblast cells, PDH deficiency zebrafish and wild type mice. PB has also shown efficacy in many cancers and so far, all of its anti-tumor activity has been attributed to the histone deacetylase (HDAC) inhibition. As PDK1/PDH controls the critical switch between oxidative phosphorylation and glycolysis in cancer cells, PDK1 is a key target in tumor metabolism for anti-cancer treatment. We hypothesize that the therapeutic effects of PB in cancers might also depend on suppressing PDK1 and promoting PDH activity, in addition to its proposed role as HDAC inhibitor. We showed that PB directly inhibited the kinase activity of PDK1 and increased the activity of PDH in an enzyme assay. In several different cancer cell lines, PB reduced the phosphorylation level of PDH, increased the mitochondrial respiration, decreased glycolysis in cytoplasm, reversed mitochondrial hyperpolarization, activated several proteins in apoptotic signaling pathway and then induced the apoptosis of cells. In summary, this is the first study indicated that PB could exert its anti-cancer effects through inhibiting PDK1, altering the mitochondrial bioenergetics and inducing apoptosis.

KeywordPhenyl Butyrate Cancer Pyruvate Dehydrogenase Pyruvate Dehydrogenase Kinase 1 Tumor Metabolism
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Indexed BySCI ; CPCI
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000414696100012
The Source to ArticleWOS
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Cited Times [WOS]:8   [WOS Record]     [Related Records in WOS]
Document TypeConference paper
CollectionFaculty of Health Sciences
AffiliationFaculty of Health and Sciences, University of Macau, Macau, China
First Author AffilicationUniversity of Macau
Recommended Citation
GB/T 7714
Zhang, Wen,Zhang, Shao-Lin,Hu, Xiaohui,et al. Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti-cancer effect[C]. PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS:ELSEVIER SCIENCE BV,2017:93-100.
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