Paclitaxel promotes a caspase 8-mediated apoptosis through death effector domain association with microtubules.
Microtubule-perturbing drugs have become front-line chemotherapeutics, inducing cell-cycle crisis as a major mechanism of action. However, these agents show pleiotropic effects on cells and can induce apoptosis through other means. Paclitaxel, a microtubule-stabilizing agent, induces a caspase-dependent apoptosis, although the precise mechanism(s) remain unclear. Here, we used genetic approaches to evaluate the role of caspase 8 in paclitaxel-mediated apoptosis. We observed that caspase 8-expressing cells are more sensitive to paclitaxel than caspase 8-deficient cells. Mechanistically, caspase 8 was found associated with microtubules, and this interaction increased after paclitaxel treatment. The prodomains death effector domains (DEDs) of caspase 8 were sufficient for interaction with microtubules, but the caspase 8 holoprotein was required for apoptosis. DED-only forms of caspase 8 were found in both primary and tumor cell lines, associating with perinuclear microtubules and the centrosome. Microtubule association, and paclitaxel sensitivity, depends on a critical lysine (K156) within a microtubule-binding motif (KLD) in DED-b of caspase 8. The results show an unexpected pathway of apoptosis mediated by caspase 8.
Mielgo
A
A
Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Torres
V A
VA
Clair
K
K
Barbero
S
S
Stupack
D G
DG
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000737:chemistry / Q000502:physiology*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000502:physiology; D006801:Humans; D008870:Microtubules / Q000502:physiology*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D017434:Protein Structure, Tertiary
D000972:Antineoplastic Agents, Phytogenic; D053181:Caspase 8; D017239:Paclitaxel