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First published online 26 October 2004
doi: 10.1242/jcs.01490

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FLICE/caspase-8 activation triggers anoikis induced by ß₁-integrin blockade in human keratinocytes

Alessandra Marconi^1,*, Paola Atzei^1,*, Cristina Panza¹, Chiara Fila¹, Rossana Tiberio², Francesca Truzzi¹, Tina Wachter³, Martin Leverkus³ and Carlo Pincelli^1,

¹ Institute of Dermatology, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy
² Institute of Dermatology, University of Piemonte Orientale, Novara, Italy
³ Department of Dermatology, University of Würzburg Medical School, Josef-Schneider-Str. 2, 97070 Würzburg, Germany

Author for correspondence (e-mail: carlo{at}unimo.it)

Accepted 10 August 2004

ß₁-integrin protects keratinocyte stem cells (KSC) from cell-detachment apoptosis (`anoikis'). Here we show that caspase-8 active protein is detected in both young transit amplifying (TA) cells and TA cells, but not in KSC. On suspension, caspases are activated earlier in young TA than in KSC, whereas anti-ß₁-integrin neutralizing antibody accelerates caspase activation in both KSC and young TA. Caspases 8 and 10 are the first caspases to be activated whereas caspase-8 inhibitor zIETD-fmk delays the activation of Bid, caspase-9 and caspase-3. However, the caspase-9 inhibitor zLEDH-fmk does not block the activation of caspase-8, Bid, caspase-10 and caspase-3. Moreover, caspase-8, but not caspase-9 inhibitor partially prevents keratinocyte anoikis. As FLIP inhibits caspase-8 processing, we retrovirally infected HaCaT keratinocytes with c-FLIP_L. Anti-ß₁-integrin fails to activate caspase-8, Bid, caspase-9 and to induce the release of cytochrome c in c-FLIP_L overexpressing keratinocytes. Finally, overexpression of c-FLIP_L partially prevents anoikis in both suspended and anti-ß₁ integrin-treated cells. Taken together, these results indicate that the extrinsic apoptotic pathway triggered by caspase-8 predominates in keratinocyte anoikis. However, the release of cytochrome c and the later activation of caspase-9 seem to suggest that the intrinsic mitochondrial pathway may intervene as a positive feedback loop of caspase activation.

Key words: Keratinocyte, Anoikis, Integrin, Caspase, cFLIP, Stem cell

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