Initiation of apoptosis by actin cytoskeletal derangement in human airway epithelial cells

Changes in epithelial cell shape can lead to cell death and detachment. Act in filaments are cleaved during apoptosis, but whether disruption in the ac tin cytoskeletal network, as one manifestation of cell shape change, can it self induce apoptosis is not known. We tested this hypothesis in the airway epithelial cell line 1HAEo(-) and in primary airway epithelial cells by pr eventing actin filament elongation with cytochalasin D or by aggregating ac tin filaments with jasplakinolide. Disruption of actin filament integrity p romptly induced apoptosis in adherent epithelial cells within 5 h. Jasplaki nolide-induced apoptosis did not disrupt focal adhesions, whereas cytochala sin D-induced apoptosis decreased focal adhesion protein expression and occ urred despite ligation of the fibronectin receptor. Death induction was abr ogated by the caspase inhibitors z-VAD-fmk and Ac-DEVD-cho but not by block ing the Fas (CD95) receptor. Whereas cytochalasin D-induced apoptosis was a ssociated with cleavage of pro-caspase-8, jasplakinolide-induced apoptosis; was not. Both agents induced formation of a death-inducing signaling comple x. These data demonstrate that disruption of actin filament integrity with either cytochalasin D or jasplakinolide induces apoptosis in airway epithel ial cells but by different mechanisms, and suggest that actin may be an ear ly modulator of apoptotic commitment.