Temporospatial sequence of cellular events associated with etoposide-induced neuronal cell death: Role of antiapoptotic protein Bcl-XL

Ji Eun Kim, Baek S. Han, Won Seok Choi, Dae Seok Eom, Eun Hee Lee, Tae H. Oh, George J. Markelonis, Takaomi C. Saido, Gun Eui Lee, In Kwon Chung, Young Jun Oh

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Etoposide-induced death comprises such nuclear events as the formation of topoisomerase II-DNA cleavable complex and cytosolic events including caspase activation. By first establishing the temporospatial death sequence triggered by etoposide in a neuronal cell line, MN9D overexpressing Bcl-XL (MN9D/Bcl-XL) or control vector (MN9D/Neo), we examined whether formation of this complex is primarily responsible for cell death and at which strategic points and how Bcl-XL blocks etoposide-induced neuronal death. Etoposide induced death that was dependent on caspase, cycloheximide, and calpain in MN9D/Neo cells. Etoposide also induced death in enucleated MN9D/Neo cells, although this was less severe. The level of topoisomerase II-DNA cleavable complex reached at a maximum of 2 hr after etoposide treatment was identical in MN9D/Neo and MN9D/Bcl-XL cells. In MN9D/Neo cells, cytochrome c release into the cytosol and caspase activation occurred as early as 2 hr and 3-6 hr after etoposide treatment, respectively. Etoposide-induced DNA laddering potentially via caspase appeared as early as 12 hr after drug treatment, followed by nuclear swelling in MN9D/Neo cells (>18-20 hr). Subsequently, nuclear condensation started by 24-28 hr and became apparent thereafter. All of these events except for nuclear swelling were substantially blocked in MN9D/Bcl-XL. At the later stage of cell death (<32-36 hr), a specific cleavage of Bax and fodrin appeared that was completely blocked by calpain inhibitor or by Bcl-XL. Taken together, our data suggest that Bcl-XL prevents etoposide-induced neuronal death by exerting its anticaspase and anticalpain effect on cellular events after the formation of topoisomerase II-DNA cleavable complex that may not be a major contributor to cell death.

Original languageEnglish
Pages (from-to)1074-1082
Number of pages9
JournalJournal of Neuroscience Research
Volume66
Issue number6
DOIs
Publication statusPublished - 2001 Dec 15

Fingerprint

bcl-X Protein
Etoposide
Cell Death
Caspases
Type II DNA Topoisomerase
Calpain
Cycloheximide
Cytochromes c
Cytosol

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

Cite this

Kim, Ji Eun ; Han, Baek S. ; Choi, Won Seok ; Eom, Dae Seok ; Lee, Eun Hee ; Oh, Tae H. ; Markelonis, George J. ; Saido, Takaomi C. ; Lee, Gun Eui ; Chung, In Kwon ; Oh, Young Jun. / Temporospatial sequence of cellular events associated with etoposide-induced neuronal cell death : Role of antiapoptotic protein Bcl-XL. In: Journal of Neuroscience Research. 2001 ; Vol. 66, No. 6. pp. 1074-1082.
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abstract = "Etoposide-induced death comprises such nuclear events as the formation of topoisomerase II-DNA cleavable complex and cytosolic events including caspase activation. By first establishing the temporospatial death sequence triggered by etoposide in a neuronal cell line, MN9D overexpressing Bcl-XL (MN9D/Bcl-XL) or control vector (MN9D/Neo), we examined whether formation of this complex is primarily responsible for cell death and at which strategic points and how Bcl-XL blocks etoposide-induced neuronal death. Etoposide induced death that was dependent on caspase, cycloheximide, and calpain in MN9D/Neo cells. Etoposide also induced death in enucleated MN9D/Neo cells, although this was less severe. The level of topoisomerase II-DNA cleavable complex reached at a maximum of 2 hr after etoposide treatment was identical in MN9D/Neo and MN9D/Bcl-XL cells. In MN9D/Neo cells, cytochrome c release into the cytosol and caspase activation occurred as early as 2 hr and 3-6 hr after etoposide treatment, respectively. Etoposide-induced DNA laddering potentially via caspase appeared as early as 12 hr after drug treatment, followed by nuclear swelling in MN9D/Neo cells (>18-20 hr). Subsequently, nuclear condensation started by 24-28 hr and became apparent thereafter. All of these events except for nuclear swelling were substantially blocked in MN9D/Bcl-XL. At the later stage of cell death (<32-36 hr), a specific cleavage of Bax and fodrin appeared that was completely blocked by calpain inhibitor or by Bcl-XL. Taken together, our data suggest that Bcl-XL prevents etoposide-induced neuronal death by exerting its anticaspase and anticalpain effect on cellular events after the formation of topoisomerase II-DNA cleavable complex that may not be a major contributor to cell death.",
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Temporospatial sequence of cellular events associated with etoposide-induced neuronal cell death : Role of antiapoptotic protein Bcl-XL. / Kim, Ji Eun; Han, Baek S.; Choi, Won Seok; Eom, Dae Seok; Lee, Eun Hee; Oh, Tae H.; Markelonis, George J.; Saido, Takaomi C.; Lee, Gun Eui; Chung, In Kwon; Oh, Young Jun.

In: Journal of Neuroscience Research, Vol. 66, No. 6, 15.12.2001, p. 1074-1082.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Temporospatial sequence of cellular events associated with etoposide-induced neuronal cell death

T2 - Role of antiapoptotic protein Bcl-XL

AU - Kim, Ji Eun

AU - Han, Baek S.

AU - Choi, Won Seok

AU - Eom, Dae Seok

AU - Lee, Eun Hee

AU - Oh, Tae H.

AU - Markelonis, George J.

AU - Saido, Takaomi C.

AU - Lee, Gun Eui

AU - Chung, In Kwon

AU - Oh, Young Jun

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N2 - Etoposide-induced death comprises such nuclear events as the formation of topoisomerase II-DNA cleavable complex and cytosolic events including caspase activation. By first establishing the temporospatial death sequence triggered by etoposide in a neuronal cell line, MN9D overexpressing Bcl-XL (MN9D/Bcl-XL) or control vector (MN9D/Neo), we examined whether formation of this complex is primarily responsible for cell death and at which strategic points and how Bcl-XL blocks etoposide-induced neuronal death. Etoposide induced death that was dependent on caspase, cycloheximide, and calpain in MN9D/Neo cells. Etoposide also induced death in enucleated MN9D/Neo cells, although this was less severe. The level of topoisomerase II-DNA cleavable complex reached at a maximum of 2 hr after etoposide treatment was identical in MN9D/Neo and MN9D/Bcl-XL cells. In MN9D/Neo cells, cytochrome c release into the cytosol and caspase activation occurred as early as 2 hr and 3-6 hr after etoposide treatment, respectively. Etoposide-induced DNA laddering potentially via caspase appeared as early as 12 hr after drug treatment, followed by nuclear swelling in MN9D/Neo cells (>18-20 hr). Subsequently, nuclear condensation started by 24-28 hr and became apparent thereafter. All of these events except for nuclear swelling were substantially blocked in MN9D/Bcl-XL. At the later stage of cell death (<32-36 hr), a specific cleavage of Bax and fodrin appeared that was completely blocked by calpain inhibitor or by Bcl-XL. Taken together, our data suggest that Bcl-XL prevents etoposide-induced neuronal death by exerting its anticaspase and anticalpain effect on cellular events after the formation of topoisomerase II-DNA cleavable complex that may not be a major contributor to cell death.

AB - Etoposide-induced death comprises such nuclear events as the formation of topoisomerase II-DNA cleavable complex and cytosolic events including caspase activation. By first establishing the temporospatial death sequence triggered by etoposide in a neuronal cell line, MN9D overexpressing Bcl-XL (MN9D/Bcl-XL) or control vector (MN9D/Neo), we examined whether formation of this complex is primarily responsible for cell death and at which strategic points and how Bcl-XL blocks etoposide-induced neuronal death. Etoposide induced death that was dependent on caspase, cycloheximide, and calpain in MN9D/Neo cells. Etoposide also induced death in enucleated MN9D/Neo cells, although this was less severe. The level of topoisomerase II-DNA cleavable complex reached at a maximum of 2 hr after etoposide treatment was identical in MN9D/Neo and MN9D/Bcl-XL cells. In MN9D/Neo cells, cytochrome c release into the cytosol and caspase activation occurred as early as 2 hr and 3-6 hr after etoposide treatment, respectively. Etoposide-induced DNA laddering potentially via caspase appeared as early as 12 hr after drug treatment, followed by nuclear swelling in MN9D/Neo cells (>18-20 hr). Subsequently, nuclear condensation started by 24-28 hr and became apparent thereafter. All of these events except for nuclear swelling were substantially blocked in MN9D/Bcl-XL. At the later stage of cell death (<32-36 hr), a specific cleavage of Bax and fodrin appeared that was completely blocked by calpain inhibitor or by Bcl-XL. Taken together, our data suggest that Bcl-XL prevents etoposide-induced neuronal death by exerting its anticaspase and anticalpain effect on cellular events after the formation of topoisomerase II-DNA cleavable complex that may not be a major contributor to cell death.

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