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10.1371/journal.pone.0183871 http://scihub22266oqcxt.onion/10.1371/journal.pone.0183871 C5571985!5571985 !28841710     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28841710 &cmd=llinks): Failed to open stream: HTTP request failed! 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Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer |pdf=|usr=}}{{28841710 }} gab.com Text Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer JO: PLoS One http://www.kidney.de/pget.php?&tw=1&pmid=28841710 #FOAvip ROCK, or Rho-associated coiled coil-containing protein kinase, is a member of the AGC kinase family and has been shown to play a role in cell migration, ECM synthesis, stress-fiber assembly, and cell contraction. Increased ROCK expression has been reported in multiple pathological conditions, including cancer. Here, we report increased expression of ROCK 1 in pancreatic tumor epithelial cells as well as in cancer associated fibroblasts (CAF). In our analysis, 62% of tumor samples exhibited ?2+ in staining intensity by IHC analysis, versus 40% of adjacent normal tissue samples (P<0.0001). Thus, we hypothesized that ROCKs may play a significant role in pancreatic cancer progression, and may serve as a suitable target for treatment. We report a low frequency (4/34) amplification of the ROCK1 gene locus at chromosome 18q11.1 in pancreatic ductal adenocarcinoma (PDAC) patient tissue samples by aCGH analysis. Inhibition of ROCK kinase activity by a small molecule inhibitor (fasudil) resulted in moderate (IC50s of 6-71 ?M) inhibition of PDAC cell proliferation, migration, and activation of co-cultured stellate cells. In the KPC mouse model for pancreatic cancer, fasudil decreased tumor collagen deposition. This translated to an enhanced overall survival of the mice and an increase in gemcitabine uptake. Though fasudil may target both the tumor epithelial cells and the CAFs, our findings are consistent with the hypothesis that inhibition of tumor stroma enhances drug penetration and efficacy in PDAC. Overall, our data suggests that ROCK1 may serve as a potential therapeutic target to enhance current treatment regimens for pancreatic cancer. Twit Text FOAVip Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer ????PLoS One http://www.kidney.de/pget.php?&tw=1&pmid=28841710 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28841710 #FOAvip English Wikipedia <ref>{{Cite pmid|28841710 }}</ref> Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer #MMPMID28841710 Whatcott CJ ; Ng S ; Barrett MT ; Hostetter G ; Von Hoff DD ; Han H PLoS One 2017[]; 12 (8 ): e0183871 PMID28841710 show ga ROCK, or Rho-associated coiled coil-containing protein kinase, is a member of the AGC kinase family and has been shown to play a role in cell migration, ECM synthesis, stress-fiber assembly, and cell contraction. Increased ROCK expression has been reported in multiple pathological conditions, including cancer. Here, we report increased expression of ROCK 1 in pancreatic tumor epithelial cells as well as in cancer associated fibroblasts (CAF). In our analysis, 62% of tumor samples exhibited ?2+ in staining intensity by IHC analysis, versus 40% of adjacent normal tissue samples (P<0.0001). Thus, we hypothesized that ROCKs may play a significant role in pancreatic cancer progression, and may serve as a suitable target for treatment. We report a low frequency (4/34) amplification of the ROCK1 gene locus at chromosome 18q11.1 in pancreatic ductal adenocarcinoma (PDAC) patient tissue samples by aCGH analysis. Inhibition of ROCK kinase activity by a small molecule inhibitor (fasudil) resulted in moderate (IC50s of 6-71 ?M) inhibition of PDAC cell proliferation, migration, and activation of co-cultured stellate cells. In the KPC mouse model for pancreatic cancer, fasudil decreased tumor collagen deposition. This translated to an enhanced overall survival of the mice and an increase in gemcitabine uptake. Though fasudil may target both the tumor epithelial cells and the CAFs, our findings are consistent with the hypothesis that inhibition of tumor stroma enhances drug penetration and efficacy in PDAC. Overall, our data suggests that ROCK1 may serve as a potential therapeutic target to enhance current treatment regimens for pancreatic cancer. |Animals [MESH] |Carcinoma, Pancreatic Ductal/enzymology/genetics/*pathology [MESH] |Comparative Genomic Hybridization [MESH] |Gene Silencing [MESH] |Humans [MESH] |Mice [MESH] |Neoplasm Metastasis [MESH] |Pancreatic Neoplasms/enzymology/genetics/*pathology [MESH] |RNA, Small Interfering/genetics [MESH] |Stromal Cells/*pathology [MESH]Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibr(epmc).pdf DeepDyve Pubget Overpricing