Complestatin prevents apoptotic cell death: Inhibition of a mitochondrial caspase pathway through AKT/PKB activation

Eok Cheon Kim; Bong Sik Yun; In Ja Ryoo; Jeong Ki Min; Moo Ho Won; Kwang Soon Lee; Young Myeong Kim; Ick Dong Yoo; Young Guen Kwon

doi:10.1016/j.bbrc.2003.11.104

Complestatin prevents apoptotic cell death: Inhibition of a mitochondrial caspase pathway through AKT/PKB activation

Eok Cheon Kim, Bong Sik Yun, In Ja Ryoo, Jeong Ki Min, Moo Ho Won, Kwang Soon Lee, Young Myeong Kim, Ick Dong Yoo, Young Guen Kwon

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Complestatin, a bicyclo hexapeptide from Streptomyces, was isolated as a possible regulator of neuronal cell death. In this study, we report an anti-apoptotic activity of complestatin and its underlying molecular mechanism. Complestatin blocked TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis and activation of caspase-3 and -8 at micromolar concentration levels without inhibiting the catalytic activities of these caspases. Complestatin potently induced a rapid and sustained AKT/PKB activation and Bad phosphorylation, resulting in inhibition of mitochondrial cytochrome c release. These anti-apoptotic activities of complestatin were significantly abrogated in cells expressing dominant negative AKT/PKB. Taken together, our results suggest that complestatin prevents apoptotic cell death via AKT/PKB-dependent inhibition of the mitochondrial apoptosis signal pathway. The novel property of complestatin may be valuable for developing new pharmaceutical means that will control unwanted cell death.

Original language	English
Pages (from-to)	193-204
Number of pages	12
Journal	Biochemical and Biophysical Research Communications
Volume	313
Issue number	1
DOIs	https://doi.org/10.1016/j.bbrc.2003.11.104
Publication status	Published - 2004 Jan 2

Bibliographical note

Funding Information:
We extend our sincere thanks to Dr. Timothy R. Billiar (University of Pittsburgh) for providing HA-AKT and DN-AKT expression vector. We thank Dr. James A. Bibb (University of Texas Southwestern) for critical reading of the manuscript. This work was supported by G7 and NRL grants (to I.-D.Y.) and a Vascular System Research Center grant (to Y.-G.K.), Ministry of Science and Technology, Republic of Korea.

All Science Journal Classification (ASJC) codes

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.bbrc.2003.11.104

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title = "Complestatin prevents apoptotic cell death: Inhibition of a mitochondrial caspase pathway through AKT/PKB activation",

abstract = "Complestatin, a bicyclo hexapeptide from Streptomyces, was isolated as a possible regulator of neuronal cell death. In this study, we report an anti-apoptotic activity of complestatin and its underlying molecular mechanism. Complestatin blocked TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis and activation of caspase-3 and -8 at micromolar concentration levels without inhibiting the catalytic activities of these caspases. Complestatin potently induced a rapid and sustained AKT/PKB activation and Bad phosphorylation, resulting in inhibition of mitochondrial cytochrome c release. These anti-apoptotic activities of complestatin were significantly abrogated in cells expressing dominant negative AKT/PKB. Taken together, our results suggest that complestatin prevents apoptotic cell death via AKT/PKB-dependent inhibition of the mitochondrial apoptosis signal pathway. The novel property of complestatin may be valuable for developing new pharmaceutical means that will control unwanted cell death.",

author = "Kim, {Eok Cheon} and Yun, {Bong Sik} and Ryoo, {In Ja} and Min, {Jeong Ki} and Won, {Moo Ho} and Lee, {Kwang Soon} and Kim, {Young Myeong} and Yoo, {Ick Dong} and Kwon, {Young Guen}",

note = "Funding Information: We extend our sincere thanks to Dr. Timothy R. Billiar (University of Pittsburgh) for providing HA-AKT and DN-AKT expression vector. We thank Dr. James A. Bibb (University of Texas Southwestern) for critical reading of the manuscript. This work was supported by G7 and NRL grants (to I.-D.Y.) and a Vascular System Research Center grant (to Y.-G.K.), Ministry of Science and Technology, Republic of Korea.",

year = "2004",

month = jan,

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doi = "10.1016/j.bbrc.2003.11.104",

language = "English",

volume = "313",

pages = "193--204",

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T1 - Complestatin prevents apoptotic cell death

T2 - Inhibition of a mitochondrial caspase pathway through AKT/PKB activation

AU - Kim, Eok Cheon

AU - Yun, Bong Sik

AU - Ryoo, In Ja

AU - Min, Jeong Ki

AU - Won, Moo Ho

AU - Lee, Kwang Soon

AU - Kim, Young Myeong

AU - Yoo, Ick Dong

AU - Kwon, Young Guen

N1 - Funding Information: We extend our sincere thanks to Dr. Timothy R. Billiar (University of Pittsburgh) for providing HA-AKT and DN-AKT expression vector. We thank Dr. James A. Bibb (University of Texas Southwestern) for critical reading of the manuscript. This work was supported by G7 and NRL grants (to I.-D.Y.) and a Vascular System Research Center grant (to Y.-G.K.), Ministry of Science and Technology, Republic of Korea.

PY - 2004/1/2

Y1 - 2004/1/2

N2 - Complestatin, a bicyclo hexapeptide from Streptomyces, was isolated as a possible regulator of neuronal cell death. In this study, we report an anti-apoptotic activity of complestatin and its underlying molecular mechanism. Complestatin blocked TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis and activation of caspase-3 and -8 at micromolar concentration levels without inhibiting the catalytic activities of these caspases. Complestatin potently induced a rapid and sustained AKT/PKB activation and Bad phosphorylation, resulting in inhibition of mitochondrial cytochrome c release. These anti-apoptotic activities of complestatin were significantly abrogated in cells expressing dominant negative AKT/PKB. Taken together, our results suggest that complestatin prevents apoptotic cell death via AKT/PKB-dependent inhibition of the mitochondrial apoptosis signal pathway. The novel property of complestatin may be valuable for developing new pharmaceutical means that will control unwanted cell death.

AB - Complestatin, a bicyclo hexapeptide from Streptomyces, was isolated as a possible regulator of neuronal cell death. In this study, we report an anti-apoptotic activity of complestatin and its underlying molecular mechanism. Complestatin blocked TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis and activation of caspase-3 and -8 at micromolar concentration levels without inhibiting the catalytic activities of these caspases. Complestatin potently induced a rapid and sustained AKT/PKB activation and Bad phosphorylation, resulting in inhibition of mitochondrial cytochrome c release. These anti-apoptotic activities of complestatin were significantly abrogated in cells expressing dominant negative AKT/PKB. Taken together, our results suggest that complestatin prevents apoptotic cell death via AKT/PKB-dependent inhibition of the mitochondrial apoptosis signal pathway. The novel property of complestatin may be valuable for developing new pharmaceutical means that will control unwanted cell death.

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Complestatin prevents apoptotic cell death: Inhibition of a mitochondrial caspase pathway through AKT/PKB activation

Abstract

Bibliographical note

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