Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells

Cancer Res. 2005 Aug 15;65(16):7292-300. doi: 10.1158/0008-5472.CAN-05-0775.

Abstract

Galectin-3 (Gal-3), a pleiotropic carbohydrate-binding protein, is a selective binding partner of activated K-Ras-GTP. Because both proteins are antiapoptotic and associated with cancer progression, we questioned the possible functional role of Gal-3 in K-Ras activation. We found that overexpression of Gal-3 in human breast cancer cells (BT-549/Gal-3) coincided with a significant increase in wild-type (wt) K-Ras-GTP coupled with loss in wt N-Ras-GTP, whereas the nononcogenic Gal-3 mutant proteins [Gal-3(S6E) and Gal-3(G182A)] failed to induce the Ras isoform switch. Only wt Gal-3 protein coimmunoprecipitated and colocalized with oncogenic K-Ras, resulting in its activation with radical alterations in Ras signaling pathway, whereby the activation of AKT and Ral was suppressed and shifted to the activation of extracellular signal-regulated kinase (ERK). Specific inhibitors for Ras or mitogen-activated protein/ERK kinase (farnesylthiosalicylic acid and UO126, respectively) inhibited Gal-3-mediated apoptotic resistance and anchorage-independent growth functions. In conclusion, this study shows that Gal-3 confers on BT-549 human breast carcinoma cells several oncogenic functions by binding to and activation of wt K-Ras, suggesting that some of the molecular functions of Gal-3 are, at least in part, a result of K-Ras activation.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Galectin 3 / biosynthesis
  • Galectin 3 / genetics
  • Galectin 3 / physiology*
  • Humans
  • MAP Kinase Signaling System
  • Mutation
  • Protein Isoforms
  • ras Proteins / biosynthesis*
  • ras Proteins / genetics

Substances

  • Galectin 3
  • Protein Isoforms
  • ras Proteins