Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer
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. Previou...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/6/1654 |
| _version_ | 1797612987722235904 |
|---|---|
| author | Benjamin L. Woolbright Ganeshkumar Rajendran Erika Abbott Austin Martin Ryan Didde Katie Dennis Robert A. Harris John A. Taylor |
| author_facet | Benjamin L. Woolbright Ganeshkumar Rajendran Erika Abbott Austin Martin Ryan Didde Katie Dennis Robert A. Harris John A. Taylor |
| author_sort | Benjamin L. Woolbright |
| collection | DOAJ |
| description | 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<sup>−/−</sup> 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<sup>−/−</sup> mice had significantly larger tumors at later time points. When animals were treated with cisplatin, PDK4<sup>−/−</sup> 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. |
| first_indexed | 2024-03-11T06:49:33Z |
| format | Article |
| id | doaj.art-61402c4090434a4ab7d787cb6467412b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T06:49:33Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-61402c4090434a4ab7d787cb6467412b2023-11-17T10:05:20ZengMDPI AGCancers2072-66942023-03-01156165410.3390/cancers15061654Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder CancerBenjamin L. Woolbright0Ganeshkumar Rajendran1Erika Abbott2Austin Martin3Ryan Didde4Katie Dennis5Robert A. Harris6John A. Taylor7Department of Urology, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Urology, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Urology, University of Kansas Medical Center, Kansas City, KS 66160, USASchool of Medicine, Kansas University Medical Center, Kansas City, KS 66160, USASchool of Medicine, Kansas University Medical Center, Kansas City, KS 66160, USADepartment of Pathology, Kansas University Medical Center, Kansas City, KS 66160, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Urology, University of Kansas Medical Center, Kansas City, KS 66160, USAPyruvate 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<sup>−/−</sup> 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<sup>−/−</sup> mice had significantly larger tumors at later time points. When animals were treated with cisplatin, PDK4<sup>−/−</sup> 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.https://www.mdpi.com/2072-6694/15/6/1654bladder cancermousePDK4BBNPDH |
| spellingShingle | Benjamin L. Woolbright Ganeshkumar Rajendran Erika Abbott Austin Martin Ryan Didde Katie Dennis Robert A. Harris John A. Taylor Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer Cancers bladder cancer mouse PDK4 BBN PDH |
| title | Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer |
| title_full | Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer |
| title_fullStr | Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer |
| title_full_unstemmed | Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer |
| title_short | Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer |
| title_sort | pyruvate dehydrogenase kinase 4 deficiency increases tumorigenesis in a murine model of bladder cancer |
| topic | bladder cancer mouse PDK4 BBN PDH |
| url | https://www.mdpi.com/2072-6694/15/6/1654 |
| work_keys_str_mv | AT benjaminlwoolbright pyruvatedehydrogenasekinase4deficiencyincreasestumorigenesisinamurinemodelofbladdercancer AT ganeshkumarrajendran pyruvatedehydrogenasekinase4deficiencyincreasestumorigenesisinamurinemodelofbladdercancer AT erikaabbott pyruvatedehydrogenasekinase4deficiencyincreasestumorigenesisinamurinemodelofbladdercancer AT austinmartin pyruvatedehydrogenasekinase4deficiencyincreasestumorigenesisinamurinemodelofbladdercancer AT ryandidde pyruvatedehydrogenasekinase4deficiencyincreasestumorigenesisinamurinemodelofbladdercancer AT katiedennis pyruvatedehydrogenasekinase4deficiencyincreasestumorigenesisinamurinemodelofbladdercancer AT robertaharris pyruvatedehydrogenasekinase4deficiencyincreasestumorigenesisinamurinemodelofbladdercancer AT johnataylor pyruvatedehydrogenasekinase4deficiencyincreasestumorigenesisinamurinemodelofbladdercancer |