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Published 2 August 2004. doi:10.1083/jcb.200312074
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 3, 419-431
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Article

 Switch from {alpha}vß5 to {alpha}vß6 integrin expression protects squamous cell carcinomas from anoikis

Sam M. Janes and Fiona M. Watt

Keratinocyte Laboratory, CR-UK London Research Institute, London WC2A 3PX, England, UK

Address correspondence to F.M. Watt, Keratinocyte Laboratory, CR-UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, England. Tel.: 44 20 7269 3528. Fax: 44 20 7269 3078. email: fiona.watt{at}cancer.org.uk

Stratified squamous epithelia express the {alpha}vß5 integrin, but in squamous cell carcinomas (SCCs) there is down-regulation of {alpha}vß5 and up-regulation of {alpha}vß6. To investigate the significance of this finding, we transduced an {alpha}v-negative human SCC line with retroviral vectors encoding {alpha}v integrins. {alpha}vß5-expressing cells underwent suspension-induced apoptosis (anoikis), whereas {alpha}v-negative cells and cells expressing {alpha}vß6 did not. Resistance to anoikis correlated with PKB/Akt activation in suspension, but not with changes in PTEN or p110{alpha} PI3 kinase levels. Anoikis was induced in parental and {alpha}vß6-expressing cells by inhibiting PI3 kinase. Conversely, activation of Akt or inhibition of caspases in {alpha}vß5-expressing cells suppressed anoikis. Caspase inhibition resulted in increased phosphoAkt, placing caspase activation upstream of decreased Akt activation. Anoikis required the cytoplasmic domain of ß5 and was independent of the death receptor pathway. These results suggest that down-regulation of {alpha}vß5 through up-regulation of {alpha}vß6 may protect SCCs from anoikis by activating an Akt survival signal.

Key Words: keratinocyte; apoptosis; differentiation; Akt; extracellular matrix

Abbreviations used in this paper: dn, dominant-negative; ER, estrogen receptor; OHT, 4-hydroxytamoxifen; SCC, squamous cell carcinoma.


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