Abstract
Loss of the Adenomatous Polyposis Coli (APC) tumor suppressor in colorectal cancer elicits rapid signaling through the Wnt/β-catenin signaling pathway. In contrast to this well-established role of APC, recent studies from our laboratory demonstrated that APC functions through Wnt-independent pathways to mediate in vitro and in vivo models of breast tumorigenesis. Pancreatic ductal adenocarcinoma (PDAC) has an overall median survival of less than one year with a 5-year survival rate of 7.2%. APC is lost in a subset of pancreatic cancers, but the impact on Wnt signaling or tumor development is unclear. Given the lack of effective treatment strategies for pancreatic cancer, it is important to understand the functional implications of APC loss in pancreatic cancer cell lines. Therefore, the goal of this project is to study how APC loss affects Wnt pathway activation and in vitro tumor phenotypes. Using lentiviral shRNA, we successfully knocked down APC expression in six pancreatic cancer cell lines (AsPC-1, BxPC3, L3.6pl, HPAF-II, Hs 766T, MIA PaCa-2). No changes were observed in localization of β-catenin or reporter assays to assess β-catenin/TCF interaction. Despite this lack of Wnt/β-catenin pathway activation, the majority of APC knockdown cell lines exhibit an increase in cell proliferation. Cell migration assays showed that the BxPC-3 and L3.6pl cells were impacted by APC knockdown, showing faster wound healing in scratch wound assays. Interestingly, APC knockdown had no effect on gemcitabine treatment, which is the standard care for pancreatic cancer. It is important to understand the functional implications of APC loss in pancreatic cancer cells lines, which could be used as a target for therapeutics.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) has an overall median survival of less than one year and is the third leading cause of cancer-related deaths for both men and women in the United States [1].Patients are often asymptomatic early on, which results in approximately 53% of patients being diagnosed in advanced stages
We successfully knocked down Adenomatous Polyposis Coli (APC) in six pancreatic ductal adenocarcinoma cell lines; AsPC-1, BxPC-3, HPAF-II, Hs 766T, L3.6pl, and MIA PaCa-2. β-catenin localization was at the cell–cell junctions and not nuclear, suggesting that the Wnt pathway is not active, which is similar to previously published data [20]
Proliferation was significantly increased after APC knockdown in BxPC-3 and L3.6pl at 48 h and in Hs 766T at 48 and 72 h compared to CTL
Summary
Pancreatic ductal adenocarcinoma (PDAC) has an overall median survival of less than one year and is the third leading cause of cancer-related deaths for both men and women in the United States [1]. Patients are often asymptomatic early on, which results in approximately 53% of patients being diagnosed in advanced stages. The five-year survival rate for advanced stage PDAC is 7.2% [2]. Death rates due to pancreatic cancer are rising for both men and women [1]. Treatments for patients with PDAC include surgery or chemotherapy treatments using a DNA nucleoside, gemcitabine [3]. These treatment options may relieve symptoms or extend survival, they
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