Cord Blood Stem Cell-Mediated Induction of Apoptosis in Glioma Downregulates X-Linked Inhibitor of Apoptosis Protein (XIAP)
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BACKGROUND: XIAP (X-linked inhibitor of apoptosis protein) is one of the most important members of the apoptosis inhibitor family. XIAP is upregulated in various malignancies, including human glioblastoma. It promotes invasion, metastasis, growth and survival of malignant cells. We hypothesized that downregulation of XIAP by human umbilical cord blood mesenchymal stem cells (hUCBSC) in glioma cells would cause them to undergo apoptotic death. METHODOLOGY/PRINCIPAL FINDINGS: We observed the effect of hUCBSC on two malignant glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310). In co-cultures of glioma cells with hUCBSC, proliferation of glioma cells was significantly inhibited. This is associated with increased cytotoxicity of glioma cells, which led to glioma cell death. Stem cells induced apoptosis in glioma cells, which was evaluated by TUNEL assay, FACS analyses and immunoblotting. The induction of apoptosis is associated with inhibition of XIAP in co-cultures of hUCBSC. Similar results were obtained by the treatment of glioma cells with shRNA to downregulate XIAP (siXIAP). Downregulation of XIAP resulted in activation of caspase-3 and caspase-9 to trigger apoptosis in glioma cells. Apoptosis is characterized by the loss of mitochondrial membrane potential and upregulation of mitochondrial apoptotic proteins Bax and Bad. Cell death of glioma cells was marked by downregulation of Akt and phospho-Akt molecules. We observed similar results under in vivo conditions in U251- and 5310-injected nude mice brains, which were treated with hUCBSC. Under in vivo conditions, Smac/DIABLO was found to be colocalized in the nucleus, showing that hUCBSC induced apoptosis is mediated by inhibition of XIAP and activation of Smac/DIABLO. CONCLUSIONS/SIGNIFICANCE: Our results indicate that downregulation of XIAP by hUCBSC treatment induces apoptosis, which led to the death of the glioma cells and xenograft cells. This study demonstrates the therapeutic potential of XIAP and hUCBSC to treat malignant gliomas.
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MSC-derived secretome promotes cell cycle arrest and induction of apoptosis through upregulation of pro-apoptotic Bax and p21, and downregulation of anti-apoptotic Bcl2, Survivin and Xiap genes.
“MSC-derived secretome promote cell cycle arrest and induction of apoptosis through the upregulation of pro-apoptotic Bax gene and negative regulator of cell cycle such as p21, and downregulation of anti-apoptotic Bcl2, Survinin and Xiap genes [108], [109], [110], [111], [112].”
From Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? (2025) · cites this paper as [109]
The Results section (‘Co-culture of glioma cells with hUCBSC downregulates XIAP’; page unavailable) reports apoptosis alongside increased Bax protein and decreased Bcl-2 protein; the Discussion reports loss of XIAP protein. The study examined stem-cell co-cultures, not an isolated MSC secretome, and these passages do not establish gene-expression changes, p21 upregulation, survivin downregulation, or cell-cycle arrest. (LLM, conf=0.89)
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- Authors
- Dasari, V. R., Velpula, K. K., Kaur, K., Fassett, D., Klopfenstein, J. D., Dinh, D. H., Gujrati, M., & Rao, J. S.
- Affiliations
- Peoria campus of the University of Illinois System (US)
- Corresponding author
- Rao, Jasti S.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-07-28
- Volume
- 5
- Issue
- 7
- Pages
- e11813
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2911373
- OpenAlex
- W1992270919
- Cited by
- 87
- References
- 62
- Citations by year
- 2025: 5 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 10 · 2020: 4 · 2019: 9 · 2018: 5 · 2017: 5 · 2015: 9 · 2014: 4 · 2013: 4 · 2012: 7
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2025-07-11)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Neurological Disorders and Stroke (NS057529, R01NS057529)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- XIAP, glioma, glioblastoma, umbilical cord blood mesenchymal stem cells, apoptosis, stem cell therapy, caspase-3, caspase-9, Smac/DIABLO, Akt signaling, Bax, Bad, mitochondrial apoptosis, xenograft tumor growth
- MeSH terms
- Animals, Fetal Blood, Flow Cytometry, Glioma, Humans, Stem Cells, Immunoblotting, Apoptosis, In Situ Nick-End Labeling, Cord Blood Stem Cell Transplantation, Cell Line, Tumor, Mice, X-Linked Inhibitor of Apoptosis Protein, Caspase 3, Caspase 9
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