Regulation of Bax by c-Jun NH2-terminal kinase and Bcl-xL in vinblastine-induced apoptosis

Rong Chu, Meenakshi Upreti, Wen Xing Ding, Xiao-Ming Yin, Timothy C. Chambers

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Microtubule inhibitors, such as vinblastine, are widely used in cancer chemotherapy. Vinblastine exerts its antitumor effect by inducing apoptosis. In KB-3 cells, we have shown previously that vinblastine activates c-Jun NH2-terminal protein kinase (JNK) and causes Bax mitochondrial translocation and activation. In this study, we sought to test the hypothesis that JNK and Bcl-xL act as positive and negative regulators, respectively, of Bax translocation. The JNK inhibitor SP600125 inhibited vinblastine-induced JNK activation and in concert inhibited Bax mitochondrial translocation, Bax oligomerization, and Bax activation. Furthermore, the JNK inhibitor blocked vinblastine-induced apoptosis. The ability of vinblastine to induce Bax translocation and the inhibitory effect of SP600125 were confirmed in cells stably expressing GFP-Bax. However, if transiently overexpressed, Bax localized to the mitochondria, and this was associated with loss of viability and subsequent cell death. If Bcl-xL was co-expressed with Bax, the cells readily tolerated Bax overexpression. Indeed, physical interaction between Bcl-xL and Bax but not Bak was demonstrated by co-immunoprecipitation. These findings provide novel insight into the role of Bax and its regulation in vinblastine-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)241-248
Number of pages8
JournalBiochemical Pharmacology
Volume78
Issue number3
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

Fingerprint

Vinblastine
JNK Mitogen-Activated Protein Kinases
Apoptosis
Protein Kinases
Chemical activation
Protein Kinase Inhibitors
KB Cells
Oligomerization
Mitochondria
Chemotherapy
Cell death
Immunoprecipitation
Microtubules
Cell Death
Drug Therapy
Neoplasms

Keywords

  • Apoptosis
  • Bax
  • Bcl-xL
  • JNK
  • Vinblastine

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Regulation of Bax by c-Jun NH2-terminal kinase and Bcl-xL in vinblastine-induced apoptosis. / Chu, Rong; Upreti, Meenakshi; Ding, Wen Xing; Yin, Xiao-Ming; Chambers, Timothy C.

In: Biochemical Pharmacology, Vol. 78, No. 3, 01.08.2009, p. 241-248.

Research output: Contribution to journalArticle

Chu, Rong ; Upreti, Meenakshi ; Ding, Wen Xing ; Yin, Xiao-Ming ; Chambers, Timothy C. / Regulation of Bax by c-Jun NH2-terminal kinase and Bcl-xL in vinblastine-induced apoptosis. In: Biochemical Pharmacology. 2009 ; Vol. 78, No. 3. pp. 241-248.
@article{74a908142edb4dfa9acf7b11bc5e4d9b,
title = "Regulation of Bax by c-Jun NH2-terminal kinase and Bcl-xL in vinblastine-induced apoptosis",
abstract = "Microtubule inhibitors, such as vinblastine, are widely used in cancer chemotherapy. Vinblastine exerts its antitumor effect by inducing apoptosis. In KB-3 cells, we have shown previously that vinblastine activates c-Jun NH2-terminal protein kinase (JNK) and causes Bax mitochondrial translocation and activation. In this study, we sought to test the hypothesis that JNK and Bcl-xL act as positive and negative regulators, respectively, of Bax translocation. The JNK inhibitor SP600125 inhibited vinblastine-induced JNK activation and in concert inhibited Bax mitochondrial translocation, Bax oligomerization, and Bax activation. Furthermore, the JNK inhibitor blocked vinblastine-induced apoptosis. The ability of vinblastine to induce Bax translocation and the inhibitory effect of SP600125 were confirmed in cells stably expressing GFP-Bax. However, if transiently overexpressed, Bax localized to the mitochondria, and this was associated with loss of viability and subsequent cell death. If Bcl-xL was co-expressed with Bax, the cells readily tolerated Bax overexpression. Indeed, physical interaction between Bcl-xL and Bax but not Bak was demonstrated by co-immunoprecipitation. These findings provide novel insight into the role of Bax and its regulation in vinblastine-induced apoptosis.",
keywords = "Apoptosis, Bax, Bcl-xL, JNK, Vinblastine",
author = "Rong Chu and Meenakshi Upreti and Ding, {Wen Xing} and Xiao-Ming Yin and Chambers, {Timothy C.}",
year = "2009",
month = "8",
day = "1",
doi = "10.1016/j.bcp.2009.04.005",
language = "English (US)",
volume = "78",
pages = "241--248",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Regulation of Bax by c-Jun NH2-terminal kinase and Bcl-xL in vinblastine-induced apoptosis

AU - Chu, Rong

AU - Upreti, Meenakshi

AU - Ding, Wen Xing

AU - Yin, Xiao-Ming

AU - Chambers, Timothy C.

PY - 2009/8/1

Y1 - 2009/8/1

N2 - Microtubule inhibitors, such as vinblastine, are widely used in cancer chemotherapy. Vinblastine exerts its antitumor effect by inducing apoptosis. In KB-3 cells, we have shown previously that vinblastine activates c-Jun NH2-terminal protein kinase (JNK) and causes Bax mitochondrial translocation and activation. In this study, we sought to test the hypothesis that JNK and Bcl-xL act as positive and negative regulators, respectively, of Bax translocation. The JNK inhibitor SP600125 inhibited vinblastine-induced JNK activation and in concert inhibited Bax mitochondrial translocation, Bax oligomerization, and Bax activation. Furthermore, the JNK inhibitor blocked vinblastine-induced apoptosis. The ability of vinblastine to induce Bax translocation and the inhibitory effect of SP600125 were confirmed in cells stably expressing GFP-Bax. However, if transiently overexpressed, Bax localized to the mitochondria, and this was associated with loss of viability and subsequent cell death. If Bcl-xL was co-expressed with Bax, the cells readily tolerated Bax overexpression. Indeed, physical interaction between Bcl-xL and Bax but not Bak was demonstrated by co-immunoprecipitation. These findings provide novel insight into the role of Bax and its regulation in vinblastine-induced apoptosis.

AB - Microtubule inhibitors, such as vinblastine, are widely used in cancer chemotherapy. Vinblastine exerts its antitumor effect by inducing apoptosis. In KB-3 cells, we have shown previously that vinblastine activates c-Jun NH2-terminal protein kinase (JNK) and causes Bax mitochondrial translocation and activation. In this study, we sought to test the hypothesis that JNK and Bcl-xL act as positive and negative regulators, respectively, of Bax translocation. The JNK inhibitor SP600125 inhibited vinblastine-induced JNK activation and in concert inhibited Bax mitochondrial translocation, Bax oligomerization, and Bax activation. Furthermore, the JNK inhibitor blocked vinblastine-induced apoptosis. The ability of vinblastine to induce Bax translocation and the inhibitory effect of SP600125 were confirmed in cells stably expressing GFP-Bax. However, if transiently overexpressed, Bax localized to the mitochondria, and this was associated with loss of viability and subsequent cell death. If Bcl-xL was co-expressed with Bax, the cells readily tolerated Bax overexpression. Indeed, physical interaction between Bcl-xL and Bax but not Bak was demonstrated by co-immunoprecipitation. These findings provide novel insight into the role of Bax and its regulation in vinblastine-induced apoptosis.

KW - Apoptosis

KW - Bax

KW - Bcl-xL

KW - JNK

KW - Vinblastine

UR - http://www.scopus.com/inward/record.url?scp=65749090235&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65749090235&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2009.04.005

DO - 10.1016/j.bcp.2009.04.005

M3 - Article

C2 - 19427996

AN - SCOPUS:65749090235

VL - 78

SP - 241

EP - 248

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 3

ER -