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J. Biol. Chem., Vol. 279, Issue 46, 48342-48349, November 12, 2004

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Squamous Cell Carcinoma Cell Aggregates Escape Suspension-induced, p53-mediated Anoikis

FIBRONECTIN AND INTEGRIN _v MEDIATE SURVIVAL SIGNALS THROUGH FOCAL ADHESION KINASE^*

Yan Zhang, Hai Lu, Paul Dazin¶, and Yvonne Kapila||

From the Department of Stomatology, School of Dentistry, and ^¶Howard Hughes Medical Institute, School of Medicine, University of California, San Francisco, California 94143

Resistance to anoikis, or apoptosis triggered by detachment from the extracellular matrix (ECM), lengthens the survival of malignant cells, facilitating reattachment and colonization of secondary sites. To examine the molecular mechanisms underlying resistance to anoikis in human oral squamous cell carcinoma (SCC) cells, we cultured human squamous carcinoma (HSC-3) cells in suspension on plates coated with poly-2-hydroxyethyl methacrylate, which blocks access to the ECM. Cells in suspension that formed multicellular aggregates had significantly lower levels of apoptosis than single cells. Aggregates, but not single cells, had high levels of fibronectin. Preincubation with a cyclic arginine-glycine-aspartic acid peptide or fibronectin-blocking antibody significantly increased anoikis. Single cells had markedly lower expression of the integrin _v receptor than aggregates. Blocking _v function with a blocking antibody or by transfection with an antisense oligonucleotide increased apoptosis and inhibited aggregation. In single cells but not aggregates, phosphorylation of the integrin-associated focal adhesion kinase (FAK) at tyrosine 397 was reduced, and p53 levels were increased. Apoptosis was increased by blocking FAK with an antisense oligonucleotide and reduced by blocking p53. These findings show that SCC cells escape suspension-induced anoikis by forming multicellular aggregates that avail themselves of fibronectin survival signals mediated by integrin _v. Single cells in suspension that do not form aggregates undergo anoikis because of decreased FAK phosphorylation and increased p53 levels. Thus, SCC cells appear to use neighboring cells and the ECM molecule FN to promote the metastatic phenotype.

Received for publication, July 14, 2004 , and in revised form, August 17, 2004.

^* This work was supported by National Institutes of Health Grants R01 DE14429 and P01 DE13904 (to Y. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: University of Michigan, School of Dentistry, Dept. of Periodontics/Prevention/Geriatrics, 1011 N. University Ave., Rm. 5213, Ann Arbor, MI 48109-1078. Tel.: 734-615-2295; Fax: 734-763-5503; E-mail: ykapila{at}umich.edu.

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