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p38 Mitogen-activated protein kinases is required for counteraction of 2-methoxyestradiol to estradiol-stimulated cell proliferation and induction of apoptosis in ovarian carcinoma cells via phosphorylation Bcl-2

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Abstract

Introduction: 2-Methoxyestradiol (2ME2), a natural endogenous product of estradiol (E2) metabolism, has been shown to be a selective apoptotic agent for cancer cells but not for normal cells. In this study, we determined that 2ME2 counteracts E2-stimulated cell growth and induces apoptosis in ovarian carcinoma cells. In addition, we demonstrate that 2ME2 induces apoptosis via p38 and phospho-Bcl2 pathway.

Methods: 2ME2 and/or E2 were administered to the OVCAR-3 (human ovarian cancer) cell line. Cell growth inhibition was analyzed by [3H] Thymidine incorporation assay and DNA fluorometric assay. Cell apoptosis was tested by DNA fragmentation analysis and FACS. The signaling pathway was determined by a series of biochemical assays.

Results: 2ME2 inhibited estradiol-stimulated cell growth and induced apoptosis in an ovarian carcinoma cell line. MAPK and p38, but not JNK, were found to be critical mediators in this process. Expression of a dominant negative mutant of p38 kinase or p38 specific inhibitor, SB 203580, almost completely blocked the process. Furthermore, Bcl-2 phosphorylation was required for 2ME2-induced effects.

Conclusion: Our data suggest that 2ME2 inhibits E2-stimulated proliferation and induces apoptosis in ovarian carcinoma cells. Furthermore, activation of p38 and phosphorylation of Bcl-2 plays a critical role in the mechanism. 2ME2 therefore, may have a clinical application for the treatment of ovarian cancer.

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Authors and Affiliations

  1. Department of Physiology, Basic Medicine College Second Military Medical University, Shanghai, P.R.China

    S. Z. Bu, Y. Hou, J. W. Wang & X. Ni

  2. Department of Immunology, Basic Medicine College Second Military Medical University, Shanghai, P.R.China

    Y. M. Jiang

  3. Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, P.R.China

    Q. Huang & Z. Y. Guo

  4. Department of Pathology, 455 Hospital, Shanghai, P.R.China

    H. B. Min

  5. Institute of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R.China

    J. F. Wei & S. S. Zheng

  6. Department of Endocrinology, Changhai Hospital, 174# Changhai Road, Shanghai, 200433, P.R.China

    Q. Huang

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  1. S. Z. Bu
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Correspondence to Q. Huang.

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Drs. ShiZhong Bu and Qin Huang contributed equally to this manuscript

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Bu, S.Z., Huang, Q., Jiang, Y.M. et al. p38 Mitogen-activated protein kinases is required for counteraction of 2-methoxyestradiol to estradiol-stimulated cell proliferation and induction of apoptosis in ovarian carcinoma cells via phosphorylation Bcl-2. Apoptosis 11, 413–425 (2006). https://doi.org/10.1007/s10495-006-4064-z

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