Decrease in survival threshold of quiescent colon carcinoma cells in the presence of a small molecule integrin antagonist

Mol Pharmacol. 2003 Jun;63(6):1281-8. doi: 10.1124/mol.63.6.1281.

Abstract

The role of adhesion molecules, such as alphav integrins, in the control of the survival of quiescent tumor cells is unclear. We used S 34961, a novel small molecule alphav integrin antagonist, to investigate the role of integrin-signaling in the survival of populations of quiescent human HT-29 and HCT 116 colon carcinoma cells. S 34961 at 1 microM induced detachment, but cells retained viability, existing as clusters. Nonligated beta-integrins may recruit and activate caspase-8 [J Cell Biol 155:459-470, 2001]. However, congruent with the absence of apoptosis, no activation of caspase-8 in these cells was detected after incubation with S 34961. A rapid (2 h) change in conformation of the N terminus of proapoptotic Bak was observed before detachment, together with a decrease in phosphorylation of focal adhesion kinase (2 h) and subsequent (8 h) decreases in phosphorylation of extracellular signal-regulated kinase-1/2 and Akt. Together, these results suggested that although treatment with S 34961 has no effect on survival per se, it may reduce the survival threshold of the tumor cells, with Bak in an activated state. Indeed, concomitant incubation of S 34961 with 10 microM U-0126 (a mitogen-activated protein kinase kinase inhibitor) was found to lead to apoptosis (at 24 h), whereas U-0126 alone had no effect. Together, these observations could guide the use of combination therapy with integrin antagonists in the clinic.

MeSH terms

  • Apoptosis
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Cell Adhesion
  • Cell Survival / drug effects
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / pathology*
  • Cycloheptanes / pharmacology*
  • Enzyme Activation
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • HT29 Cells
  • Humans
  • Integrin alpha5 / drug effects
  • Integrin alpha5 / metabolism*
  • Integrins / antagonists & inhibitors*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / metabolism
  • Pyridines / pharmacology*
  • bcl-2 Homologous Antagonist-Killer Protein

Substances

  • 7-((4-(pyridin-2-ylamino)-butyrylamino)-methyl)-6,9-dihydro-5H-benzocyclohepten-5-yl-acetic acid hydrochloride
  • BAK1 protein, human
  • Cycloheptanes
  • Integrin alpha5
  • Integrins
  • Membrane Proteins
  • Pyridines
  • bcl-2 Homologous Antagonist-Killer Protein
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human
  • Mitogen-Activated Protein Kinases
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases