The oncogenic kinase Pim-1 is modulated by K-Ras signaling and mediates transformed growth and radioresistance in human pancreatic ductal adenocarcinoma cells

Carcinogenesis. 2011 Apr;32(4):488-95. doi: 10.1093/carcin/bgr007. Epub 2011 Jan 24.

Abstract

Oncogenic Pim-1 kinase is upregulated in multiple solid cancers, including human pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with few useful treatment options. Pim-1 is also transcriptionally induced upon oncogenic K-Ras-mediated transformation of the human pancreatic ductal epithelial (HPDE) cell model of PDAC. Given the near ubiquitous presence of mutant K-Ras in PDAC and its critical role in this disease, we wished to study the effects of oncogenic K-Ras signaling on Pim-1 expression, as well as the role of Pim-1 in growth transformation of PDAC cells. Pim-1 protein levels were upregulated in both PDAC cell lines and patient tumor tissues. Furthermore, ectopic oncogenic K-Ras increased Pim-1 expression in human pancreatic nestin-expressing (HPNE) cells, a distinct immortalized cell model of PDAC. Conversely, shRNA-mediated suppression of oncogenic K-Ras decreased Pim-1 protein in PDAC cell lines. These results indicate that oncogenic K-Ras regulates Pim-1 expression. The kinase activity of Pim-1 is constitutively active. Accordingly, shRNA-mediated suppression of Pim-1 in K-Ras-dependent PDAC cell lines decreased Pim-1 activity, as measured by decreased phosphorylation of the pro-apoptotic protein Bad and increased expression of the cyclin-dependent kinase inhibitor p27Kip1. Biological consequences of inhibiting Pim-1 expression included decreases in both anchorage-dependent and -independent cell growth, invasion through Matrigel and radioresistance as measured by standard clonogenic assays. These results indicate that Pim-1 is required for PDAC cell growth, invasion and radioresistance downstream of oncogenic K-Ras. Overall, our studies help to elucidate the role of Pim-1 in PDAC growth transformation and validate Pim-1 kinase as a potential molecular marker for mutated K-Ras activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Adenocarcinoma / radiotherapy
  • Carcinoma, Pancreatic Ductal / pathology*
  • Carcinoma, Pancreatic Ductal / radiotherapy
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p27 / analysis
  • Humans
  • Neoplasm Invasiveness
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / radiotherapy
  • Phosphorylation
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-pim-1 / analysis
  • Proto-Oncogene Proteins c-pim-1 / physiology*
  • Proto-Oncogene Proteins p21(ras)
  • Radiation Tolerance*
  • Signal Transduction / physiology*
  • bcl-Associated Death Protein / metabolism
  • ras Proteins / physiology*

Substances

  • BAD protein, human
  • CDKN1B protein, human
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • bcl-Associated Death Protein
  • Cyclin-Dependent Kinase Inhibitor p27
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins