Pancreatic ductal
adenocarcinoma (PDAC) is the eighth largest cause of
cancer-related mortality across the world, with a median 5-year survival rate of less than 3.5%. This is partly because the molecules and the molecular mechanisms that contribute to PDAC are not well understood. Our goal is to understand the role of
p21-activated kinase 1 (Pak1) signaling axis in the progression of PDAC. Pak1, a
serine/threonine kinase, is a well-known regulator of cytoskeletal remodeling, cell motility, cell proliferation and cell survival. Recent reports suggest that Pak1 by itself can have an oncogenic role in a wide variety of
cancers. In this study, we analyzed the expression of Pak1 in human
pancreatic cancer tissues and found that Pak1 levels are significantly upregulated in PDAC samples as compared with adjacent normals. Further, to study the functional role of Pak1 in
pancreatic cancer model systems, we developed stable overexpression and lentiviral
short hairpin RNA-mediated knockdown (KD) clones of Pak1 and studied the changes in transforming properties of the cells. We also observed that Pak1 KD clones failed to form
tumors in nude mice. By adopting a quantitative PCR array-based approach, we identified
fibronectin, a component of the extracellular matrix and a mesenchymal marker, as a transcriptional target of Pak1 signaling. The underlying molecular mechanism of Pak1-mediated transformation includes its nuclear import and recruitment to the
fibronectin promoter via interaction with nuclear factor-κB (NF-κB)-p65 complex. To our knowledge, this is the first study illustrating Pak1-NF-κB-p65-mediated
fibronectin regulation as a potent
tumor-promoting mechanism in KRAS intact model.