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Mol Pharmacol 63:1281-1288, 2003

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Decrease in Survival Threshold of Quiescent Colon Carcinoma Cells in the Presence of a Small Molecule Integrin Antagonist

Mike F. Burbridge, Virginie Venot, Patrick J. Casara, Françoise Perron-Sierra, John A. Hickman, and Gordon C. Tucker

Cancer Research Division (M.F.B., V.V., J.A.H., G.C.T.) and Chemistry Division I (P.J.C., F.P.-S.), Institut de Recherches Servier, Paris, France

The role of adhesion molecules, such as {alpha}v integrins, in the control of the survival of quiescent tumor cells is unclear. We used S 34961, a novel small molecule {alpha}v 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 µM 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 µM 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.

Received September 23, 2002; accepted March 5, 2003

Address correspondence to: Dr. Mike F. Burbridge, Cancer Research Division, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy sur Seine, Paris, France. E-mail: mike.burbridge{at}fr.netgrs.com




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