Characterizing PDK4 and PKC-Theta in Pancreatic Cancer and Cachexia

Cachexia is an involuntary wasting syndrome that cannot be reversed by nutritional support. It affects most patients with pancreatic ductal adenocarcinoma (PDAC) and is believed to cause 20% of cancer-associated deaths. Cachectic patients exhibit both metabolic abnormalities and systemic inflammation. Pyruvate Dehydrogenase Kinase 4 (PDK4) is upregulated in the skeletal muscles of many cancer cachexia models and has been shown to drive muscle wasting in some conditions. We show that despite being upregulated in an orthotopic mouse model of PDAC cachexia, whole-body deletion of PDK4 did not prevent the decline in muscle function or the overall wasting. Expression of the other members of the PDK family did not change, ruling out a compensatory mechanism. Deletion of PDK4 did not affect the dysregulated expression of metabolic and catabolic genes in PDAC cachexia. Analysis of publicly available muscle-expression datasets from cachectic cancer patients further revealed that PDK4 is not upregulated in patients' skeletal muscles. Protein Kinase C theta (PKCθ) is a lipid-sensitive kinase expressed in skeletal muscle where it regulates insulin signaling. It is also expressed in T cells, and its deletion alleviates inflammation in several inflammatory conditions. We found that PKCθ expression increases in skeletal muscle but decreases in the spleen in PDAC cachexia as the disease progresses. To delineate its role in PDAC cachexia, we generated mouse models with skeletal muscle-specific, T cell-specific, and whole-body deletion of PKCθ. Deletion of PKCθ did not substantially affect body weight or composition at baseline in any of these models. It also did not affect the wasting or tumor burden in PDAC cachexia. PKCθ-deficient T cells maintained their ability to infiltrate PDAC tumors. Overall, our work shows that despite being upregulated, PDK4 is not required for PDAC cachexia, and PKCθ is dispensable for both wasting and inflammation in this context.

Author dc:creator

• Gaafer, Omnia Usama Mohammed Shawky

Advisor dc:contributor.advisor

• Wells, Clark D.

• Cachexia
• Cancer
• PDAC
• PDK4
• PKC-theta
• rpea1

Language dc:language.iso

en_US

Identifier URI

https://doi.org/10.7912/6E37-7275

OAI identifier oai:identifier

oai:scholarworks.indianapolis.iu.edu:1805/52606