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Title:
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 Research and Treatment
Description:
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.
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Keywords {🔍}
cancer, article, google, scholar, pubmed, cas, apoptosis, breast, cells, inhibitor, smac, cell, inflammatory, res, protein, xiap, mimetic, birinapant, devi, xlinked, death, usa, trail, lyerly, ciap, wang, treatment, allensworth, sum, access, van, research, induces, nfkappab, mol, smacdiablo, duke, privacy, cookies, content, gayathri, ibc, iap, clin, aird, treat, biol, human, university, information,
Topics {✒️}
american cancer society-rsg-08-290-01-cce smac mimetics—small-molecule antagonists month download article/chapter apo-2l/trail-induced apoptosis smac/diablo-induced cell death smac mimetic-mediated sensitization smac-mimetic-induced apoptosis structure-based computational screening tnf-α-independent mechanism apoptosis inducer smac/diablo smac/diablo protein expression small-molecular weight inhibitor anticancer drug-induced apoptosis nf-kappab-dependent manner cellular flice-inhibitory protein bivalent smac mimetic anchorage-independent growth potential induce tnfalpha-dependent apoptosis tnf-alpha-independent apoptosis exogenous tnf-α addition induced nf-kappab nuclear factor kappab full article pdf breast cancer research pan-iap antagonism smac mimetic drugs smac mimetic enables nf-kappab activation related subjects activate nf-kappab privacy choices/manage cookies trail induces apoptosis nf-κb activation trail-induced apoptosis temozolomide-induced apoptosis gemcitabine-induced apoptosis gene expression profiling lentiviral-mediated delivery duke university chancellor x-linked inhibitor enhances chemotherapy sensitivity anchorage independent growth anchorage-independent growth inflammatory breast cancer inflammatory breast cancer small interfering rna inflammatory breast carcinoma human cancer cells apoptosis protein expression tnfalpha-dependent apoptosis
Questions {❓}
- Anderson WF, Chu KC, Chang S (2003) Inflammatory breast carcinoma and noninflammatory locally advanced breast carcinoma: distinct clinicopathologic entities?
- Wu H, Tschopp J, Lin SC (2007) Smac mimetics and TNFalpha: a dangerous liaison?
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headline:Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism
description: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.
datePublished:2012-12-07T00:00:00Z
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