Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer

Author:

Woolbright Benjamin L.1,Rajendran Ganeshkumar1,Abbott Erika1,Martin Austin2,Didde Ryan2,Dennis Katie3,Harris Robert A.4ORCID,Taylor John A.1

Affiliation:

1. Department of Urology, University of Kansas Medical Center, Kansas City, KS 66160, USA

2. School of Medicine, Kansas University Medical Center, Kansas City, KS 66160, USA

3. Department of Pathology, Kansas University Medical Center, Kansas City, KS 66160, USA

4. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Abstract

Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial isozyme in the PDK family (PDK1-4) partially responsible for phosphorylation of pyruvate dehydrogenase (PDH). Phosphorylation of PDH is thought to result in a pro-proliferative shift in metabolism that sustains growth of cancer cells. Previous data from our lab indicate the pan-PDK inhibitor dichloroacetate (DCA) or acute genetic knockdown of PDK4 blocks proliferation of bladder cancer (BCa) cells. The goal of this study was to determine the role of PDK4 in an in vivo BCa model, with the hypothesis that genetic depletion of PDK4 would impair formation of BCa. PDK4−/− or WT animals were exposed to N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 16 weeks, and tumors were allowed to develop for up to 7 additional weeks. PDK4−/− mice had significantly larger tumors at later time points. When animals were treated with cisplatin, PDK4−/− animals still had larger tumors than WT mice. PDK4 expression was assessed in human tissue and in mice. WT mice lost expression of PDK4 as tumors became muscle-invasive. Similar results were observed in human samples, wherein tumors had less expression of PDK4 than benign tissue. In summary, PDK4 has a complex, multifunctional role in BCa and may represent an underrecognized tumor suppressor.

Funder

National Cancer Institute Cancer Center Support

Leo and Anne Albert Charitable Trust

Publisher

MDPI AG

Subject

Cancer Research,Oncology

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Preclinical models of bladder cancer: BBN and beyond;Nature Reviews Urology;2024-05-20

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