Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism.
Abstract
X-linked inhibitor of apoptosis protein (XIAP), the most potent mammalian caspase
inhibitor, has been associated with acquired therapeutic resistance in inflammatory
breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor
survival rate. The second mitochondria-derived activator of caspases (Smac) protein
is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic
drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces
cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells
and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive
SUM149 (triple-negative, EGFR-activated) cells, two patient tumor-derived IBC models.
Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic
SUM149- and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP,
SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low
XIAP binding affinity (K (d) > 1 μM), we show that XIAP inhibition is necessary for
increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due
to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation,
PARP cleavage, and NF-κB activation. A modest increase in TNF-α production was seen
in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149
cells. Exogenous TNF-α addition did not increase Birinapant efficacy. Neutralizing
antibodies against TNF-α or TNFR1 knockdown did not reverse cell death. However, pan-caspase
inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant
in combination or as a single agent decreased colony formation and anchorage-independent
growth potential of IBC cells. By demonstrating that Birinapant primes cancer cells
for death in an IAP-dependent manner, these findings support the development of Smac
mimetics for IBC treatment.
Type
Journal articleSubject
Amino Acid Chloromethyl KetonesApoptosis
Caspase 8
Cell Line, Tumor
Dipeptides
Dose-Response Relationship, Drug
Gene Knockdown Techniques
Humans
Indoles
Inflammatory Breast Neoplasms
Inhibitor of Apoptosis Proteins
Intracellular Signaling Peptides and Proteins
Mitochondrial Proteins
Quinolines
Receptors, Tumor Necrosis Factor, Type I
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha
X-Linked Inhibitor of Apoptosis Protein
Permalink
https://hdl.handle.net/10161/12454Published Version (Please cite this version)
10.1007/s10549-012-2352-6Publication Info
Allensworth, Jennifer L; Sauer, Scott J; Lyerly, H Kim; Morse, Michael A; & Devi,
Gayathri R (2013). Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory
breast cancer cells in an IAP-dependent and TNF-α-independent mechanism. Breast Cancer Res Treat, 137(2). pp. 359-371. 10.1007/s10549-012-2352-6. Retrieved from https://hdl.handle.net/10161/12454.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Michael Aaron Morse
Professor of Medicine
We are studying the use of immune therapies to treat various cancers, including gastrointestinal,
breast, and lung cancers and melanoma. These therapies include vaccines based on
dendritic cells developed in our laboratory as well as vaccines based on peptides,
viral vectors, and DNA plasmids. Our group is also a national leader in the development
and use of laboratory assays for demonstrating immunologic responses to cancer vaccines.
Finally, we are developing immunotherapies based on ado

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info
Related items
Showing items related by title, author, creator, and subject.
-
The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease.
Na, Il-Kang; Lu, Sydney X; Yim, Nury L; Goldberg, Gabrielle L; Tsai, Jennifer; Rao, Uttam; Smith, Odette M; ... (22 authors) (J Clin Invest, 2010-01)Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions ... -
Hepatocyte growth factor enhances death receptor-induced apoptosis by up-regulating DR5.
Li, Yang; Fan, Xing; Goodwin, C Rory; Laterra, John; Xia, Shuli (BMC Cancer, 2008-11-07)BACKGROUND: Hepatocyte growth factor (HGF) and its receptor c-MET are commonly expressed in malignant gliomas and embryonic neuroectodermal tumors including medulloblastoma and appear to play an important role in the growth ... -
Epidermal growth factor regulates hematopoietic regeneration after radiation injury.
Doan, Phuong L; Himburg, Heather A; Helms, Katherine; Russell, J Lauren; Fixsen, Emma; Quarmyne, Mamle; Harris, Jeffrey R; ... (12 authors) (Nat Med, 2013-03)The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of ...