TY - JOUR
T1 - Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer
AU - Whatcott, Clifford J.
AU - Ng, Serina
AU - Barrett, Michael T.
AU - Hostetter, Galen
AU - Von Hoff, Daniel D.
AU - Han, Haiyong
N1 - Funding Information:
Funding:ThisworkwassupportedinpartbyaR01 (CA169281)grantandaU01(CA128454)grant fromtheNIH/NCI,agrantfromtheNational FoundationforCancerResearch,andaStandUp ToCancer-CancerResearchUK-Lustgarten FoundationPancreaticCancerDreamTeam ResearchGrant(GrantNumber:SU2C-AACR-DT-20-16).StandUpToCancerisaprogramofthe EntertainmentIndustryFoundation.Research grantsareadministeredbytheAmerican AssociationforCancerResearch,thescientific partnerofSU2C.Thefundershadnoroleinstudy design,datacollectionandanalysis,decisionto publish,orpreparationofthemanuscript.
Publisher Copyright:
© 2017 Whatcott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/8
Y1 - 2017/8
N2 - 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 μM) 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.
AB - 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 μM) 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.
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U2 - 10.1371/journal.pone.0183871
DO - 10.1371/journal.pone.0183871
M3 - Article
C2 - 28841710
AN - SCOPUS:85029152594
SN - 1932-6203
VL - 12
JO - PLoS One
JF - PLoS One
IS - 8
M1 - e0183871
ER -