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  • Original Paper
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Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells

Abstract

Drug design targeted at microtubules has led to the advent of some potent anti-cancer drugs. In the present study, we demonstrated that microtubule-binding agents (MBAs) taxol and colchicine induced immediate early gene (c-jun and ATF3) expression, cell cycle arrest, and apoptosis in the human breast cancer cell line MCF-7. To elucidate the signal transduction pathways that mediate such biological activities of MBAs, we studied the involvement of mitogen-activated protein (MAP) kinases. Treatment with taxol, colchicine, or other MBAs (vincristine, podophyllotoxin, nocodazole) stimulated the activity of c-jun N-terminal kinase 1 (JNK1) in MCF-7 cells. In contrast, p38 was activated only by taxol and none of the MBAs changed the activity of extracellular signal-regulated protein kinase 2 (ERK2). Activation of JNK1 or p38 by MBAs occurred subsequent to the morphological changes in the microtubule cytoskeleton induced by these compounds. Furthermore, baccatine III and β-lumicolchicine, inactive analogs of taxol and colchicine, respectively, did not activate JNK1 or p38. These results suggest that interactions between microtubules and MBAs are essential for the activation of these kinases. Pretreatment with the antioxidants N-acetyl-L-cysteine (NAC), ascorbic acid or vitamin E, blocked H2O2- or doxorubicin-induced JNK1 activity, but had no effect on JNK1 activation by MBAs, excluding a role for oxidative stress. However, BAPTA/AM, a specific intracellular Ca2+ chelator, attenuated JNK1 activation by taxol but not by colchicine, and had no effect on microtubule changes induced by taxol. Thus, stabilization or depolymerization of microtubules may regulate JNK1 activity via distinct downstream signaling pathways. The differential activation of MAP kinases opens up a new avenue for addressing the mechanism of action of anti-microtubule drugs.

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Abbreviations

ATF:

activation transcription factor

BAPTA/AM:

1,2-bis-(o-Aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid tetra-(acetoxymethyl)-ester

ERK:

extracellular signal-regulated protein kinase

GST:

glutathione S-transferase

JNK:

c-jun N-terminal kinase

MAPK:

mitogen-activated protein kinase

MBA:

microtubule binding agent

NAC:

N-acetyl-L-cysteine

ROI:

reactive oxygen intermediates

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Acknowledgements

The authors are grateful to Drs V Gelfand and T Ignatova for critical discussion of the manuscript. This work was supported by National Institutes of Health grants R37CA40333 (to IBR), R01-AI38649 (to T-HT) and R01-ES06887 (to ANTK). AAS is a Fellow of the Oncology Research Faculty Development Program of the National Cancer Institute.

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Shtil, A., Mandlekar, S., Yu, R. et al. Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells. Oncogene 18, 377–384 (1999). https://doi.org/10.1038/sj.onc.1202305

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