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All-trans retinoic acid potentiates Taxotere-induced cell death mediated by Jun N-terminal kinase in breast cancer cells

Oncogene volume 23, pages 426–433 (2004)Cite this article

Abstract

Taxotere is a cytotoxin effective in treating breast and prostate cancer. It stabilizes microtubules and causes catastrophic cell cycle arrest in G2/M. Taxanes also initiate apoptosis by activating signal pathways, such as the jun N-terminal kinase (JNK) pathway. Strategies aimed at potentiating cell death signaling may improve their efficacy while lessening the potential side effects. We reported that all-trans retinoic acid (ATRA) potentiated taxane-mediated cell death. Here we investigated whether ATRA potentiates cell death signaling through the JNK pathway. Activation of JNK by Taxotere 0.01, 0.1 and 1.0 μ M was observed at 24 h in adherent cells and increased at 48 h. Taxotere 0.001 μ M-induced JNK activation started after 48 h and increased at 72 h. The timing and intensity of PARP cleavage was similar to that of JNK activation. JNK activation and PARP cleavage induced by 30 nM Taxotere at 48 h were reversed by curcumin, PD169316 and SP600125, JNK inhibitors in order of progressive specificity. None of these inhibitors had an effect on p38 or ERK phosphorylation. All three inhibitors reversed Taxotere-induced phosphorylation of Bcl-2. ATRA induced JNK activation at 24, 48 and 72 h. Incubating cells with ATRA 0.01 μ M for 3 days prior to Taxotere treatment potentiated Taxotere-induced JNK activation 24 and 48 h later, an effect sustained for 72 h. Cytotoxicities from 3-day ATRA 0.01 μ M incubations were synergistic with subsequent 1-h Taxotere 0.01, 0.1 and 1.0 μ M incubations in breast cancer cell lines MCF-7 and MDA-MB-231 and in prostate cancer cell lines LNCaP and PC-3, and additive in breast cancer cell line SK-Br-3. These data demonstrate the potentiation of Taxotere-induced cell death by ATRA pretreatment in breast and prostate cancer cells, and support a mechanism through accentuated and sustained JNK activation.

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Acknowledgements

This work was supported by the State of New Jersey Commission on Cancer Research (QW), DAMD17-01-C-0343 and Aventis, Inc. (RW).

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  1. Department of Medicine, Division of Oncology/Hematology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, MSB I-596, 185 South Orange Avenue, Newark, 07103, NJ, USA

    Qin Wang & Robert Wieder

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  1. Qin Wang
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Correspondence to Robert Wieder.

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Wang, Q., Wieder, R. All-trans retinoic acid potentiates Taxotere-induced cell death mediated by Jun N-terminal kinase in breast cancer cells. Oncogene 23, 426–433 (2004). https://doi.org/10.1038/sj.onc.1207040

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