Abstract
Abstract ROCK1, or Rho-associated coiled coil-containing protein kinase 1, is a multifunctional member of the AGC (protein kinase A/G/C) kinase family that has been implicated in the modulation of stress-fiber assembly, cell-cell adhesion, cell contraction, apoptosis, cytokinesis, and in the migration and invasion of multiple cell types. Increased ROCK1 expression has been observed in a number of pathological conditions, including cancer. We identified a low frequency (4/34) amplification of the ROCK1 gene locus at chromosome 18q11.1 in pancreatic ductal adenocarcinoma (PDA) patient tissue samples by aCGH analysis. We therefore hypothesized that ROCK1 might play an important role in pancreatic cancer progression, and may serve as a suitable target in pancreatic cancer treatment. Consistent with findings in other tumor types, we observed increased expression of ROCK1 in pancreatic epithelial cells relative to the surrounding stromal cells, or adjacent normal pancreatic ductal cells, in an immunohistochemical (IHC) analysis of a pancreatic cancer tissue array. In our study, 76% (53/70) of tumor samples exhibited 2+ or greater (scale 0-3+) in staining intensity by IHC analysis, versus 40% (19/47) of adjacent normal tissue samples (P<0.0001). This same increased expression of ROCK1 in cancer cells was also observed in a coculture model of human PDA cells and primary myofibroblast cells derived from PDA tissues. Inhibition of ROCK kinase activity by small molecule inhibitors (Fasudil and Y27632) demonstrated moderate (IC50s range from 2-30 μM) inhibition of PDA cell proliferation. An increased sensitivity to ROCK1 inhibition was observed in PDA myofibroblasts, which corresponded with a decreased expression of Collagen I. These results suggest that ROCK1 may play a role in pancreatic cancer, both in the proliferation of tumor epithelial cells, as well as the development of the stromal compartment. Based on these findings we feel that ROCK1 is a potential therapeutic target in both the tumor and stromal cells in pancreatic cancer, and may provide an effective means to enhance current treatment regimens. 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 2601. doi:10.1158/1538-7445.AM2011-2601
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