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

SIMPLE SUMMARY: Pyruvate dehydrogenase kinase 4 (PDK4) is a protein that serves as a switch for how the body regulates metabolism. Prior research indicates that blocking the effect of PDK4 with some drugs slows the growth of bladder cancer cells. These experiments relied on cancer cell lines and not tumors grown in mouse models of cancer, which are more closely related to human disease. In a validated mouse model of bladder cancer, mice that did not express PDK4 were found to have larger tumors than mice expressing PDK4 at later points of tumor progression. As tumors became larger, there was a loss of expression of PDK4 in mice that normally expressed it. Human samples with bladder cancer had lower expression of PDK4 than those without bladder cancer. These data indicate that PDK4 may be an unexpected tumor suppressor in bladder cancer. 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.