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Carcinogenesis Advance Access published online on March 14, 2006
Carcinogenesis, doi:10.1093/carcin/bgl005
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received July 12, 2005
Revised January 31, 2006
Accepted February 28, 2006

CANCER BIOLOGY

Synthetic D-amino acid peptide inhibits tumor cell motility on laminin-5

Thomas C. Sroka 1, Michael E. Pennington 1, and Anne E. Cress 1 *

1 Department of Cell Biology and Anatomy, The University of Arizona, Tucson, Arizona 85724

* To whom correspondence should be addressed.
Anne E. Cress, E-mail: acress{at}azcc.arizona.edu


  Abstract

Cell motility is partially dependent on interactions between integrins and the extracellular matrix. Our previous studies have identified synthetic D-amino acid cell adhesion peptides using a combinatorial screening approach. In this study we demonstrate that HYD1 (kikmviswkg) completely blocks random haptotactic migration and inhibits invasion of prostate carcinoma cells on laminin-5. This effect is adhesion independent and reversible. The inhibition of migration by HYD1 involves a dramatic remodeling of the actin cytoskeleton resulting in increased stress fiber formation and actin colocalization with cortactin at the cell membrane. HYD1 interacts with {alpha}6{beta}1 (not {alpha}6{beta}4) and {alpha}3{beta}1 integrins and surprisingly elevates laminin-5 dependent intracellular signals including focal adhesion kinase, mitogen activated protein kinase kinase, and extracellular signal-regulated kinase. HYD1 does not contain a previously characterized binding sequence for integrins. A scrambled derivative of HYD1, called HYDS (wiksmkivkg), does not interact with the {alpha}6 or {alpha}3 integrin subunits and is not biologically active. Taken together, these results indicate that HYD1 is a biologically active integrin-targeting peptide that reversibly inhibits tumor cell migration on laminin-5 and uncouples phosphotyrosine signaling from cytoskeletal dependent migration.


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