Cell motility is a process tightly linked to tumor metastasis. The p21-activated kinases (PAKs) are modulators of cell motility commonly overexpressed and hyperactive in various malignancies. We investigated whether increased PAK2 expression and phosphorylation levels enhance cancer cell motility, thus worsening disease prognosis in non-small cell lung cancer (NSCLC). In silico analyses of publically available databases was accessed to determine the clinical relevance of PAK2 gene expression in NSCLC patient outcomes. Total and phospho-specific PAK1 and PAK2 antibodies were used to screen a panel of NSCLC cell lines. shRNA and small molecule inhibitors were utilized to assess the role of PAK1/2 kinases in augmenting tumor metastatic capacity in vitro by two and three-dimensional cell migration assays. Increased tumor PAK2 expression was associated with significantly worse survival in two unique cohorts of patients with resected lung adenocarcinoma. Phosphorylated PAK1/2 isoforms were frequently but variably expressed across 31 NSCLC cell lines, and at higher levels than in immortalized normal bronchial epithelial cells. We observed a dependency on PAK2 for cell motility specifically in cell lines with phosphorylated PAK1/2. Additionally, use of two PAK small molecule inhibitors recapitulated the effects observed in our PAK2 shRNA mediated knockdown studies. Our findings demonstrate the importance of PAK2 signaling in promoting lung cancer cell motility and are the first to link high PAK2 expression to poor clinical prognosis in lung adenocarcinoma. These data suggest that targeting PAK2 may cause an anti-migratory effect and potentially improve survival for NSCLC patients with elevated tumor PAK2 expression levels.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03262018-144420 |
| Date | 12 April 2018 |
| Creators | Bissonnette, Adam Marc |
| Contributors | Vito Quaranta, David P. Carbone, Barbara Fingleton |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03262018-144420/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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