X chromosome-linked inhibitor of apoptosis regulates cell death induction by proapoptotic receptor agonists.
Proapoptotic receptor agonists cause cellular demise through the activation of the extrinsic and intrinsic apoptotic pathways. Inhibitor of apoptosis (IAP) proteins block apoptosis induced by diverse stimuli. Here, we demonstrate that IAP antagonists in combination with Fas ligand (FasL) or the death receptor 5 (DR5) agonist antibody synergistically stimulate death in cancer cells and inhibit tumor growth. Single-agent activity of IAP antagonists relies on tumor necrosis factor-alpha signaling. By contrast, blockade of tumor necrosis factor-alpha does not affect the synergistic activity of IAP antagonists with FasL or DR5 agonist antibody. In most cancer cells, proapoptotic receptor agonist-induced cell death depends on amplifying the apoptotic signal via caspase-8-mediated activation of Bid and subsequent activation of the caspase-9-dependent mitochondrial apoptotic pathway. In the investigated cancer cell lines, induction of apoptosis by FasL or DR5 agonist antibody can be inhibited by knockdown of Bid. However, knockdown of X chromosome-linked IAP (XIAP) or antagonism of XIAP allows FasL or DR5 agonist antibody to induce activation of effector caspases efficiently without the need for mitochondrial amplification of the apoptotic signal and thus rescues the effect of Bid knockdown in these cells.
Varfolomeev
Eugene
E
Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA.
Alicke
Bruno
B
Elliott
J Michael
JM
Zobel
Kerry
K
West
Kristina
K
Wong
Harvey
H
Scheer
Justin M
JM
Ashkenazi
Avi
A
Gould
Stephen E
SE
Fairbrother
Wayne J
WJ
Vucic
Domagoj
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D000068800:Etanercept; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D020169:Caspases; D000068800:Etanercept