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

Ruby Shalom-Feuerstein1, Tomer Cooks, Avraham Raz

  • 1Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.

Cancer Research
|August 17, 2005
PubMed

Insights

Galectin-3 (Gal-3) activates wild-type K-Ras, promoting cancer progression in breast cells. This binding shifts Ras signaling, enhancing oncogenic functions and resistance to apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Galectin-3 (Gal-3) is a carbohydrate-binding protein implicated in cancer progression.
  • K-Ras-GTP is an antiapoptotic protein frequently activated in various cancers.

Purpose of the Study:

  • To investigate the functional role of Galectin-3 in K-Ras activation and its downstream effects in human breast cancer cells.
  • To determine if Gal-3 binding to K-Ras influences cancer cell signaling pathways and oncogenic functions.

Main Methods:

  • Overexpression of wild-type Gal-3 and mutant proteins in BT-549 breast cancer cells.
  • Co-immunoprecipitation and colocalization assays to assess Gal-3 and K-Ras interaction.
  • Analysis of downstream signaling pathways including AKT, Ral, and extracellular signal-regulated kinase (ERK).
  • Inhibition studies using specific Ras and MEK inhibitors (farnesylthiosalicylic acid and UO126).

Main Results:

  • Overexpression of wild-type Gal-3 increased wild-type K-Ras-GTP levels and induced a Ras isoform switch.
  • Wild-type Gal-3, but not mutant forms, co-immunoprecipitated and colocalized with K-Ras, leading to its activation.
  • Gal-3-mediated K-Ras activation suppressed AKT and Ral signaling while activating ERK signaling.
  • Inhibition of Ras or MEK pathways abrogated Gal-3-induced apoptotic resistance and anchorage-independent growth.

Conclusions:

  • Galectin-3 confers oncogenic functions to human breast carcinoma cells by binding to and activating wild-type K-Ras.
  • The molecular functions of Gal-3 in cancer progression are, at least partially, mediated through K-Ras activation.
  • Targeting the Gal-3/K-Ras interaction may represent a therapeutic strategy for breast cancer.

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