Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells

Cancer Res. 2005 Sep 1;65(17):7546-53. doi: 10.1158/0008-5472.CAN-05-1197.

Abstract

The antiapoptotic molecule galectin-3 was previously shown to regulate CD95, a member of the tumor necrosis factor (TNF) family of proteins in the apoptotic signaling pathway. Here, we question the generality of the phenomenon by studying a different member of this family of proteins [e.g., TNF-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a wide variety of cancer cells]. Overexpression of galectin-3 in J82 human bladder carcinoma cells rendered them resistant to TRAIL-induced apoptosis, whereas phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin and LY-294002) blocked the galectin-3 protecting effect. Because Akt is a major downstream PI3K target reported to play a role in TRAIL-induced apoptosis, we questioned the possible relationship between galectin-3 and Akt. Parental J82 and the control vector-transfected J82 cells (barely detectable galectin-3) exhibit low level of constitutively active Akt, resulting in sensitivity to TRAIL. On the other hand, J82 cells overexpressing galectin-3 cells expressed a high level of constitutively active Akt and were resistant to TRAIL. Moreover, the blockage of TRAIL-induced apoptosis in J82 cells seemed to be mediated by Akt through the inhibition of BID cleavage. These results suggest that galectin-3 involves Akt as a modulator molecule in protecting bladder carcinoma cells from TRAIL-induced apoptosis.

Publication types

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

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism
  • Cell Line, Tumor
  • Down-Regulation
  • Enzyme Activation
  • Galectin 3 / biosynthesis
  • Galectin 3 / genetics
  • Galectin 3 / physiology*
  • Humans
  • Intracellular Membranes / physiology
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Potentials / physiology
  • Mitochondria / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Urinary Bladder Neoplasms / enzymology*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology*

Substances

  • Apoptosis Regulatory Proteins
  • Galectin 3
  • Membrane Glycoproteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases