Abstract 223: ΔNp63α, a p53 family member protein, promotes tumor progression in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in both men and women. Targeted therapies thus far have failed to demonstrate survival advantage in PDAC and novel therapies are needed. Mutations in Ras and p53 are frequently found in PDAC and promote cancer cell survival, invasiveness and chemoresistance. In contrast, p63, an ancestral member of p53 family, is rarely mutated in cancer. ΔNp63α was shown to be overexpressed in squamous cell tumors of the lung and head and neck and thus has been implicated in carcinogenesis. We tested expression of p63 isoforms in five PDAC cell lines and investigated its role in tumor progression. Expression of p63 was determined by immunoblotting, real-time quantitative and semi-quantitative PCR in 5 PDAC cell lines. PANC-1 cells, with low levels of p63, were transfected with ΔNp63α cDNA-expressing vector. Conversely, high endogenous p63 levels in T3M4 and BxPC3 cell lines were suppressed by specific shRNA. We studied cell proliferation in a doubling assay, motility in wound assay and invasiveness in Matrigel chambers. We found that pancreatic cancer cell lines predominantly expressed ΔN isoform of p63, and specifically ΔNp63α variant. ΔNp63α protein and transcript levels were high in T3M4, BxPC3 and Colo-357 cell lines and low in ASPC-1 and PANC-1 cell lines. Interestingly, transcript levels of TAp63, a p63 variant implicated in cellular senescence and suppression of metastases, were near the detection threshold in all cell lines. Overexpression of ΔNp63α in PANC-1 cells resulted in increased proliferation and enhanced migration of those cells but had no effect on invasiveness in serum-free conditions. Incubation of ΔNp63α-expressing PANC-1 cells in presence of epidermal growth factor increased both migration and invasiveness. By contrast, shRNA knockdown of endogenous p63 in BxPC3 cells led to decreased proliferation. Silencing p63 in T3M4 cells resulted in attenuated migration in serum-free conditions and decreased migration and invasiveness in response to epidermal growth factor. Thus, ΔNp63α is a predominantly expressed isoform of p63 in PDAC cell lines. ΔNp63α plays an important role in PDAC progression and thus its associated pathways may potentially be therapeutically targeted in this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 223. doi:10.1158/1538-7445.AM2011-223