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Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells

Oncogene volume 23, pages 596–604 (2004)Cite this article

Abstract

c-Jun N-terminal kinase (JNK) is activated by diverse cell stimuli, including stress, growth factors, and cytokines. Traditionally, activation of JNK by stress treatment is thought to induce cell death. However, our recent data indicate that JNK's ability to sensitize cells to apoptosis may be, in part, cell cycle dependent. Here, we show that the majority of both paclitaxel- and UV-induced apoptosis can be inhibited by the pharmacological JNK inhibitor, SP600125, in MCF-7 cells. However, inhibition of JNK does little to reverse doxorubicin-induced apoptosis in MCF-7 cells or doxorubicin- and UV-mediated death in MDA MB-231 cells. SP treatment causes G2/M arrest of three breast cancer cell lines and results in the endoreduplication (cellular DNA content >4N) of MCF-7 and MDA MB-231 cells. These effects on cell cycle and apoptosis are not significantly altered by the inhibition of p53, indicating that JNK is functioning independently of p53. Lastly, inhibition of JNK using both SP and antisense oligonucleotides targeted to JNK1 and JNK2 reduced proliferation of all three breast cancer cell lines. Taken together, these results suggest that the activation of JNK is important for the induction of apoptosis following stresses that function at different cell cycle phases, and that basal JNK activity is necessary to promote proliferation and maintain diploidy in breast cancer cells.

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Acknowledgements

We thank Karen Helm and Michael Ashton from the UCCC Flow Cytometry Core for their assistance with FACS analysis presented herein. This work was supported in part by the Avon Breast Cancer Foundation and United States Army Medical Research and Command Grant DAMD17-99-9142 (to CLVDB). The content of this information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.

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Authors and Affiliations

  1. School of Pharmacy, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Campus Box C238, Denver, 80262, CO, USA

    Amy M Mingo-Sion, Peter M Marietta, Douglas M Wolf & Carla L Van Den Berg

  2. Isis Pharmaceuticals Inc., Carlsbad, 92008, CA, USA

    Erich Koller

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  1. Amy M Mingo-Sion
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  2. Peter M Marietta
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Correspondence to Carla L Van Den Berg.

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Mingo-Sion, A., Marietta, P., Koller, E. et al. Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells. Oncogene 23, 596–604 (2004). https://doi.org/10.1038/sj.onc.1207147

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