Dedifferentiation of adenocarcinomas by activation of phosphatidylinositol 3-kinase

Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4874-9. doi: 10.1073/pnas.96.9.4874.


Signet ring cell carcinoma is a malignant type of poorly differentiated adenocarcinomas in stomach, which is characterized by the occasional presence of signet ring-like cancer cells. We found that expression of constitutively active phosphatidylinositol 3-kinase (PI 3-kinase) in well differentiated adenocarcinoma cell lines induced the loss of cell-cell contact and some of the cells changed their shapes to signet ring cell-like, characterized by appearance of mucus droplets in the cytoplasm with well developed endplasmic reticulum and Golgi complexes. The active PI 3-kinase-expressing cells formed poorly differentiated tumors in nude mice, which were clearly different from those of the original cell lines. The PI 3-kinase activities detected in anti-phosphotyrosine immunoprecipitates were higher in several signet ring cell carcinoma-derived cell lines than in other adenocarcinoma cell lines. In addition, PI 3-kinase was found to be associated with a 200-kDa protein phosphorylated in tyrosine in 4 of 6 signet ring cells but not in other cell lines, suggesting that PI 3-kinase is possibly activated in these cells by binding to the 200-kDa protein. The 200-kDa protein-PI 3-kinase complex was exclusively fractionated in the membrane fractions. The specific activity of the PI 3-kinase immunoprecipitated with anti-phosphotyrosine antibody was approximately 3-fold higher than that with anti-PI 3-kinase antibody. These results suggest that PI 3-kinase in signet ring cell carcinoma is recruited to the membrane and activated by the binding to the 200-kDa protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Animals
  • Cell Differentiation
  • Enzyme Activation
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Signal Transduction
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Tumor Cells, Cultured


  • Phosphatidylinositol 3-Kinases