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Published on: November 27, 2016
Survivin inhibition induces human neural tumor cell death through caspase-independent and -dependent pathways
S L Shankar1, S Mani, K N O'Guin
1Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
Survivin inhibits apoptosis during development and carcinogenesis and is absent in differentiated cells. To determine whether survivin inhibition induces cell death in neural tumor cells, survivin antisense oligonucleotides (SAO) were administered to a human neuroblastoma (MSN) and an oligodendroglioma (TC620) resulting in a dose-dependent reduction in survivin protein. Although 74% of the SAO-treated MSN cells were trypan blue(+), PARP cleavage or activated caspase-3 was not observed. However nuclear translocation of AIF occurred and XIAP increased dramatically. Co-administration of z-Val-Ala-Asp(OMe)-fluoromethyl ketone (zVAD-fmk) with SAO did not inhibit cell death suggesting a caspase-independent mechanism of cell death. Propidium iodide (PI) staining revealed multiple large macronuclei with no apoptotic bodies supporting a role for survivin in cell division. By contrast, while 70% of the SAO-treated TC620 cells were trypan blue(+), PARP was cleaved, cells were TUNEL(+) and PI-staining revealed macronuclei and numerous apoptotic bodies. Co-treatment of the TC620 cells with SAO and zVAD-fmk blocked cell death. While no macronuclei or apoptotic bodies were observed there was a two-fold increase in metaphase cells. Our results suggest that survivin inhibition decreases the viability of human neural tumor cells and as a result of mitotic catastrophe, cell death can be initiated by either a classic apoptotic mechanism or a caspase-independent mechanism.
Insights
Survivin inhibition triggers cell death in neural tumors via apoptosis or caspase-independent pathways. This study explored survivin
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Survivin is a protein that inhibits apoptosis and is present during development and carcinogenesis.
- It is typically absent in differentiated cells.
- Understanding survivin's role in neural tumors is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate if inhibiting survivin induces cell death in human neuroblastoma (MSN) and oligodendroglioma (TC620) cells.
- To elucidate the mechanisms of cell death triggered by survivin inhibition.
Main Methods:
- Administration of survivin antisense oligonucleotides (SAO) to MSN and TC620 cell lines.
- Assessment of survivin protein levels, cell viability (trypan blue exclusion), apoptosis markers (PARP cleavage, activated caspase-3, TUNEL assay), and cell cycle progression (PI staining).
- Evaluation of caspase-dependent and -independent cell death pathways using a caspase inhibitor (zVAD-fmk).
Main Results:
- SAO treatment reduced survivin protein in both cell lines.
- MSN cells underwent caspase-independent cell death with nuclear translocation of AIF and increased XIAP, characterized by macronuclei.
- TC620 cells exhibited classic apoptosis (PARP cleavage, TUNEL positivity) and caspase-dependent cell death, with macronuclei and apoptotic bodies. SAO also increased metaphase arrest in TC620 cells.
Conclusions:
- Survivin inhibition reduces the viability of human neural tumor cells.
- Cell death can be initiated through either a classic apoptotic or a caspase-independent mechanism, suggesting diverse responses to survivin inhibition in neural tumors.
- These findings highlight survivin as a potential therapeutic target in neural cancers, with cell death occurring via mitotic catastrophe.
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