S100P promotes pancreatic cancer growth, survival, and invasion

Clin Cancer Res. 2005 Aug 1;11(15):5356-64. doi: 10.1158/1078-0432.CCR-05-0092.

Abstract

Purpose: In the current study, we examined the functional significance and mechanism of action of S100P in pancreatic cancer cells.

Experimental design: S100P levels were increased in Panc-1 cells, which do not express S100P, by transfection with an S100P cDNA and S100P levels were reduced in BxPC3 cells, which express high levels of S100P, by small interfering RNA gene silencing. Effects of these manipulations on cell proliferation, resistance to apoptotic insults, cell migration, and invasion were estimated in vitro using standard assays. The influences of S100P on tumor growth in vivo were studied using xenograft mouse models. To identify the mechanisms involved in these responses, coimmunoprecipitation studies were conducted with S100P with receptor for advanced glycation end products (RAGE) and the effects of inhibiting RAGE using an antagonistic peptide were analyzed.

Results: S100P levels correlated with the rates of cell proliferation, survival, migration, and invasion in both cell models in vitro. In vivo, increased S100P levels increased the growth of tumors in mice with s.c.-implanted Panc-1 cells and decreased S100P levels decreased tumor growth after orthotopic implantation of BxPC-3 cells. A direct interaction between S100P and RAGE was indicated by coimmunoprecipitation of these molecules from pancreatic cancer cells. A RAGE antagonist peptide inhibited this interaction and also inhibited the biological effects of S100P on these cells in vitro.

Conclusions: These data suggest that S100P plays a major role in the aggressiveness of pancreatic cancer that is likely mediated by its ability to activate RAGE. Thus, interference with S100P may provide a novel approach for treatment of pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Calcium-Binding Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Separation
  • Cell Survival
  • Culture Media, Conditioned / pharmacology
  • Culture Media, Serum-Free / pharmacology
  • Electrophoresis, Polyacrylamide Gel
  • Flow Cytometry
  • Gene Silencing
  • Glycation End Products, Advanced
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Nude
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Proteins / metabolism*
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Peptides / chemistry
  • RNA, Small Interfering / metabolism
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transfection

Substances

  • Calcium-Binding Proteins
  • Culture Media, Conditioned
  • Culture Media, Serum-Free
  • Glycation End Products, Advanced
  • Neoplasm Proteins
  • Peptides
  • RNA, Small Interfering
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • S100P protein, human