Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer

Clifford J. Whatcott, Serina Ng, Michael Barrett, Galen Hostetter, Daniel D. Von Hoff, Haiyong Han

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0183871
JournalPLoS One
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2017

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pancreatic neoplasms
Fibroblasts
Stromal Cells
Pancreatic Neoplasms
fibroblasts
Tumors
phosphotransferases (kinases)
Phosphotransferases
Cells
adenocarcinoma
neoplasms
Neoplasms
gemcitabine
Adenocarcinoma
epithelial cells
Cell Movement
Tissue
Military electronic countermeasures
Epithelial Cells
Cell proliferation

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer. / Whatcott, Clifford J.; Ng, Serina; Barrett, Michael; Hostetter, Galen; Von Hoff, Daniel D.; Han, Haiyong.

In: PLoS One, Vol. 12, No. 8, e0183871, 01.08.2017.

Research output: Contribution to journalArticle

Whatcott, Clifford J. ; Ng, Serina ; Barrett, Michael ; Hostetter, Galen ; Von Hoff, Daniel D. ; Han, Haiyong. / Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer. In: PLoS One. 2017 ; Vol. 12, No. 8.
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