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c-Jun-NH2-terminal kinase potentiates apoptotic cell death in response to carboplatin in B lymphoma cells

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Abstract

Purpose

Exposure to carboplatin (CBDCA) has been demonstrated to result in apoptotic and/or necrotic cell death, but molecular mechanisms underlying CBDCA-induced apoptosis or necrosis remain largely unclear. Here, we examined whether activation of c-Jun NH2-terminal kinase (JNK) modulates the mode of cell death induced by CBDCA in CD31 B lymphoma cells.

Methods

The mode of cell death (apoptosis versus necrosis) was investigated by flow cytometry using 7-amino-actinomycin D (7-AAD) and annexin-FITC probes. To evaluate the role of JNK1 in CBDCA-induced cell death, CH31 B lymphoma cells overexpressing dominant-negative form of JNK1 (dnJNK1) or constitutively active form of JNK1 (MKK7-JNK1) were established. Intracellular accumulation of superoxide anion (O2 −) was determined by flow cytometry using the fluorescent probe dihydroethidium (DHE).

Results

The CBDCA-induced primary apoptosis and secondary necrosis were abrogated in the dnJNK1-overexpressing CH31 cells, while it was somewhat enhanced in the MKK7-JNK1-overexpressing cells. In contrast, the CBDCA-induced primary necrosis was reduced by MKK7-JNK1, with a concurrent decrease in production of O2 −. The superoxide anion scavenger for butylated hydroxyanisol (BHA) partially reduced the CBDCA-induced O2 − production and necrotic, but not apoptotic, death in both wild type and dnJNK1-overexpressing CH31 cells.

Conclusions

Prolonged activation of JNK1 appears to be involved in CBDCA-induced apoptosis with prevention of necrosis induction, and the induction of necrosis appears to correlate with CBDCA-induced O2 − production, which is partially blocked by co-culture with BHA. These observations provide valuable information for understanding molecular mechanisms underlying CBDCA-induced cell death, and hopefully for the design of novel treatment modalities for patients with tumors.

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Abbreviations

CBDCA:

Carboplatin

JNK:

c-Jun NH2-terminal kinase

MAPK:

Mitogen-activated protein kinase

ROS:

Reactive oxygen species

dnJNK:

Dominant-negative JNK

BHA:

Butylated hydroxyanisol

MKK:

MAPK kinase

7-AAD:

7-Amino-actinomycin D

DHE:

Dihydroethidium

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Acknowledgments

This work was supported by a grant from the Intractable Immune System Disease Research Center of Tokyo Medical University, which is supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. We thank Dr. Lynn Heasley (Department of Medicine, University of Colorado Health Sciences Center, Denver, CO) for providing MKK7-JNK1.

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Authors and Affiliations

  1. Department of Immunology and Intractable Immunology Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan

    Eiko Takada, Kikumi Hata & Junichiro Mizuguchi

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  1. Eiko Takada
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  2. Kikumi Hata
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  3. Junichiro Mizuguchi
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Correspondence to Junichiro Mizuguchi.

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Takada, E., Hata, K. & Mizuguchi, J. c-Jun-NH2-terminal kinase potentiates apoptotic cell death in response to carboplatin in B lymphoma cells. Cancer Chemother Pharmacol 62, 569–576 (2008). https://doi.org/10.1007/s00280-007-0638-x

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  • DOI: https://doi.org/10.1007/s00280-007-0638-x

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