A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling.
Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor alpha (TNFalpha) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFalpha signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFalpha induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFalpha-mediated apoptosis.
Gaither
Alex
A
Oncology Disease Area and Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Porter
Dale
D
Yao
Yao
Y
Borawski
Jason
J
Yang
Guang
G
Donovan
Jerry
J
Sage
David
D
Slisz
Joanna
J
Tran
Mary
M
Straub
Christopher
C
Ramsey
Tim
T
Iourgenko
Vadim
V
Huang
Alan
A
Chen
Yan
Y
Schlegel
Robert
R
Labow
Mark
M
Fawell
Stephen
S
Sellers
William R
WR
Zawel
Leigh
L
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010051:Ovarian Neoplasms; D034622:RNA Interference / Q000502:physiology; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C522798:LBW242; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human