Abstract
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.
Highlights
RhoA/ROCK1 signaling has been shown to play an important role in cancer development and progression [1,2]
In this study we further explore the role of ROCK1 in the desmoplasia, chemoresistance, and progression of pancreatic ductal adenocarcinoma (PDAC) and its potential as a therapeutic target
We analyzed the tissue microarray (TMA) of PDAC samples for expression of ROCK1 using IHC staining techniques. This analysis revealed that ROCK1 was highly expressed in the majority of our tumor tissue samples, both in the tumor epithelial cells and in the surrounding stromal cells (Fig 1A)
Summary
RhoA/ROCK1 signaling has been shown to play an important role in cancer development and progression [1,2]. ROCK1 mediates the Smad-independent, TGFβ/ RhoA signaling axis, and has been shown to be an important mediator of cancer-associated fibroblast (CAF) activation and deposition of extracellular matrix (ECM) proteins in solid tumors [5,6]. The macroscopic changes described in desmoplasia arise in large part from extensive proliferation of myofibroblast cells that, upon activation, secrete extracellular matrix proteins that accumulate in the stromal compartment of solid tumors [9]. New therapies with greater efficacy are urgently needed for this disease To this end, targeting tumor desmoplasia to improve drug delivery and overcome chemoresistance is being investigated as a new therapeutic approach. In this study we further explore the role of ROCK1 in the desmoplasia, chemoresistance, and progression of PDAC and its potential as a therapeutic target
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
