Pak1 dysregulates pyruvate metabolism in PDAC cells by exerting a phosphorylation-mediated regulatory effect on PDHA1

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of pancreatic cancer with the worst prognosis. Treating PDAC poses significant challenges, as tumor cells adapt metabolic alterations to thrive in the hypoxic environment created by desmoplasia surrounding the tumor cells. p21-activated kinase (Pak1), a serine-threonine kinase is found to be upregulated in many solid tumors and promotes tumor progression via diverse signaling pathways. In this study, we focused on exploring the role of Pak1 in mediating tumor cell metabolism. Deletion of the Pak1 gene reduced the tumorigenic potential of PDAC cells. Also, Pak1 regulated both glycolysis and mitochondrial respiration in PDAC cells, contributing to the Warburg phenomenon. Untargeted metabolomic analysis revealed that Pak1 was strongly associated with pyruvate metabolism. Interestingly, we found that Pak1 interacted and phosphorylated pyruvate dehydrogenase E1α (PDHA1) at serine 152. This phosphorylation negatively regulates PDHA1 activity, implying the direct regulatory role of Pak1 in pyruvate metabolism. Moreover, deleting the Pak1 gene altered the expression and activity of PDHA1 and LDHA, as both are involved in regulating the direction of pyruvate flux inside the cells. Our study demonstrated that Pak1 plays a significant role in PDAC metabolism and Warburg effect, partly by phosphorylating PDHA1.