Decrease in survival threshold of quiescent colon carcinoma cells in the presence of a small molecule integrin antagonist.
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.
Burbridge
Mike F
MF
Cancer Research Division, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy sur Seine, Paris, France. mike.burbridge@fr.netgrs.com
Venot
Virginie
V
Casara
Patrick J
PJ
Perron-Sierra
Françoise
F
Hickman
John A
JA
Tucker
Gordon C
GC
D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002448:Cell Adhesion; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D003508:Cycloheptanes / Q000494:pharmacology*; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019073:HT29 Cells; D006801:Humans; D039482:Integrin alpha5 / Q000187:drug effects / Q000378:metabolism*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein
C474873:7-((4-(pyridin-2-ylamino)-butyrylamino)-methyl)-6,9-dihydro-5H-benzocyclohepten-5-yl-acetic acid hydrochloride; C494772:BAK1 protein, human; D003508:Cycloheptanes; D039482:Integrin alpha5; D016023:Integrins; D008565:Membrane Proteins; D011725:Pyridines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases