RT Journal Article
SR Electronic
T1 Decrease in Survival Threshold of Quiescent Colon Carcinoma Cells in the Presence of a Small Molecule Integrin Antagonist
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1281
OP 1288
DO 10.1124/mol.63.6.1281
VO 63
IS 6
A1 Mike F. Burbridge
A1 Virginie Venot
A1 Patrick J. Casara
A1 Françoise Perron-Sierra
A1 John A. Hickman
A1 Gordon C. Tucker
YR 2003
UL http://molpharm.aspetjournals.org/content/63/6/1281.abstract
AB The role of adhesion molecules, such as αv integrins, in the control of the survival of quiescent tumor cells is unclear. We used S 34961, a novel small molecule αv 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 β-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.