Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-α but not through TRAIL and FasL.
Open accessAbstract
BCG, the current gold standard immunotherapy for bladder cancer, exerts its activity via recruitment of neutrophils to the tumor microenvironment. Many patients do not respond to BCG therapy, indicating the need to understand the mechanism of action of BCG-stimulated neutrophils and to identify ways to overcome resistance to BCG therapy. Using isolated human neutrophils stimulated with BCG, we found that TNF-α is the key mediator secreted by BCG-stimulated neutrophils. RT4v6 human bladder cancer cells, which express TNFR1, CD95/Fas, CD95 ligand/FasL, DR4, and DR5, were resistant to BCG-stimulated neutrophil conditioned medium but effectively killed by the combination of conditioned medium and Smac mimetic. rhTNF-α and rhFasL, but not rhTRAIL, in combination with Smac mimetic, generated signature molecular events similar to those produced by BCG-stimulated neutrophils in combination with Smac mimetic. However, experiments using neutralizing antibodies to these death ligands showed that TNF-α secreted from BCG-stimulated neutrophils was the key mediator of anticancer action. These findings explain the mechanism of action of BCG and identified Smac mimetics as potential combination therapeutic agents for bladder cancer.
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The activated TNF pathway mediated by miR-206 can drive NF-κB to enter the nucleus and boost the creation and release of inflammatory mediators such as TNF-α, IL-8, IL-6, and others to involve in inflammatory and immunological processes.
“The activated TNF pathway mediated by miR-206 can, in turn, drive NF-κB to enter the nucleus and boost the creation and release of inflammatory mediators such as TNF-α, IL-8, IL-6, and others to involve in inflammatory and immunological processes [40].”
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- Authors
- Jinesh G., G., Chunduru, S., & Kamat, A. M.
- Affiliations
- Department of Urology, The University of Texas MD Anderson Cancer Center , Houston, Texas, USA
- TetraLogic Pharmaceuticals (United States) (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Kamat, Ashish M
- ORCID
- Kamat, Ashish M
- Venue
- Journal of Leukocyte Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-07-01
- Volume
- 92
- Issue
- 1
- Pages
- 233-244
- ISSN
- 0741-5400 (ISSN-L)
- 1938-3673
- PMC
- PMC3382315
- OpenAlex
- W2097566455
- Cited by
- 60
- References
- 41
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 9 · 2016: 10 · 2015: 5 · 2014: 6 · 2013: 4 · 2012: 3
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Leukocyte Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Clayton Foundation for Research
- MD Anderson Cancer Center
- U.S. National Institutes of Health
- MD Andersonˈs Cancer Center Support (CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- IAP antagonists, BCG immunotherapy, bladder cancer, neutrophils, TNF-α, TRAIL, Fas ligand, apoptosis, TNFR1, death receptor signaling, combination therapy, tumor microenvironment, BCG resistance
- MeSH terms
- Urinary Bladder Neoplasms, Enzyme-Linked Immunosorbent Assay, Humans, Mycobacterium bovis, Neutrophils, Oligopeptides, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Blotting, Western, Culture Media, Conditioned, Neutrophil Activation, Molecular Mimicry, Cell Proliferation, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand, Fas Ligand Protein
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