Date Published: April 5, 2017
Publisher: Public Library of Science
Author(s): Jeran K. Stratford, Feng Yan, Rebecca A. Hill, Michael B. Major, Lee M. Graves, Channing J. Der, Jen Jen Yeh, James Freeman.
Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1). We found overexpression of TTK protein in a subset of pancreatic ductal adenocarcinoma primary tumors and cell lines. siRNA-mediated depletion or catalytic inhibition of TTK resulted in an aberrant cell cycle profile, multi- and micro-nucleation, induction of apoptosis, and decreased cell proliferation and transformed growth. Selective catalytic inhibition of TTK caused override of the spindle assembly checkpoint-induced cell cycle arrest. Interestingly, we identified ubiquitin specific peptidase 16 (Usp16), an ubiquitin hydrolase, as a phosphorylation substrate of TTK. Usp16 regulates chromosomal condensation and G2/M progression by deubiquitinating histone H2A and polo-like kinase 1. Phosphomimetic mutants of Usp16 show enhanced proteosomal degradation and may prolong the G2/M transition allowing for correction of replication errors. Taken together, our results suggest a critical role for TTK in preventing aneuploidy-induced cell death in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) represents 85% of all pancreatic cancers  and is projected to be the third leading cause of cancer related deaths in the United States in 2016 . Median survival of pancreatic cancer patients is five to eight months with fewer than 5% of patients surviving longer than five years after diagnosis. The poor prognosis stems from the frequent presence of metastatic disease at the time of or shortly after diagnosis. The current standard of care for metastatic pancreatic cancer is chemotherapy. Although chemotherapeutic approaches including gemcitabine, nab-paclitaxel, and FOLFIRINOX have improved patient survival [3–5], the discovery of new and better drug targets remains essential for the continued improvement of therapies for PDAC.
An increased understanding of the biology of PDAC is essential to the identification of drug targets for the development of better therapies. Chromosomal instability and aneuploidy are characteristics of PDAC [8,60–64]. The SAC limits chromosomal instability by ensuring faithful segregation of sister chromatids during mitosis. Here we show RNA overexpression of the core components of the SAC in primary PDAC tumors compared to normal pancreas. We hypothesize that targeting the SAC function may alter the ability of cancer cells to adapt to aneuploidy and may be a possible therapy for PDAC.