Switch from αvβ5 to αvβ6 integrin expression protects squamous cell carcinomas from anoikis

Stratified squamous epithelia express the αvβ5 integrin, but in squamous cell carcinomas (SCCs) there is down-regulation of αvβ5 and up-regulation of αvβ6. To investigate the significance of this finding, we transduced an αv-negative human SCC line with retroviral vectors encoding αv integrins. αvβ5-expressing cells underwent suspension-induced apoptosis (anoikis), whereas αv-negative cells and cells expressing αvβ6 did not. Resistance to anoikis correlated with PKB/Akt activation in suspension, but not with changes in PTEN or p110α PI3 kinase levels. Anoikis was induced in parental and αvβ6-expressing cells by inhibiting PI3 kinase. Conversely, activation of Akt or inhibition of caspases in αvβ5-expressing cells suppressed anoikis. Caspase inhibition resulted in increased phosphoAkt, placing caspase activation upstream of decreased Akt activation. Anoikis required the cytoplasmic domain of β5 and was independent of the death receptor pathway. These results suggest that down-regulation of αvβ5 through up-regulation of αvβ6 may protect SCCs from anoikis by activating an Akt survival signal.