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Regulation of intracellular calcium release and PP1α in a mechanism for 4-hydroxytamoxifen-induced cytotoxicity

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Abstract

Treatment with tamoxifen, or its metabolite 4-hydroxytamoxifen (4OHT), has cytostatic and cytotoxic effects on breast cancer cells in vivo and in culture. Although the effectiveness of 4OHT as an anti-breast cancer agent is due to its action as an estrogen receptor-alpha (ERα) antagonist, evidences show that 4OHT is also cytotoxic for ERα-negative breast cancer cells and can be effective therapy against tumors that lack estrogen receptors. These findings underscore 4OHT signaling complexities and belie the most basic understandings of 4OHT action and resistance. Here, we have investigated the effects of 4OHT on Ca2+ homeostasis and cell death in breast cancer cells in culture. Measurement of Ca2+ signaling in breast cancer cells showed that 4OHT treatment altered Ca2+ homeostasis and was cytotoxic for both an ERα+ and an ERα- cell line, MCF-7 and MDA-MB-231, respectively. Further investigation lead us to the novel discovery that 4OHT-induced increase of ATP-dependent Ca2+ release from the endoplasmic reticulum correlated with 4OHT-induced upregulation of protein phosphatase 1α (PP1α) and the inositol 1,4,5-trisphosphate receptor (IP3R). Blocking 4OHT-induced PP1α upregulation by siRNA strategy reduced the effects of 4OHT on both Ca2+ signaling and cytotoxicity. Results from these investigations strongly suggest a role for PP1α upregulation in a mechanism for 4OHT-induced changes to Ca2+ signaling that ultimately contribute to the cytotoxic effects of 4OHT.

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Abbreviations

PP1α:

Protein Phosphatase 1 alpha

Ca2+ :

Calcium

EnR:

Endoplasmic reticulum

ER:

Estrogen receptor

IP3R:

Inositol 1,4,5-trisphosphate (IP3) receptor

4OHT:

4-Hydroxytamoxifen

SOCE:

Store-operated calcium entry

Tg:

Thapsigargin

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Acknowledgments

NIH grants HL-39481 (T. H. Kuo) and CA100864 (J. D. Liao).

We thank Prof. David Andrews (McMaster University, West Hamilton, ON, Canada) for providing the Bcl-2 overexpressing MCF-7 cell line.

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Authors and Affiliations

  1. Karmanos Cancer Institute, Wayne State University, 110 E Warren, HWCRC room 731, Detroit, MI, 48201, USA

    Aliccia Bollig, Archana Thakur, Jiusheng Wu & Joshua D. Liao

  2. Department of Pathology, Wayne State University, Detroit, MI, USA

    Aliccia Bollig, Liping Xu, Archana Thakur, Jiusheng Wu, Tuan H. Kuo & Joshua D. Liao

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  1. Aliccia Bollig
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  2. Liping Xu
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  3. Archana Thakur
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  6. Joshua D. Liao
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Correspondence to Joshua D. Liao.

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Aliccia Bollig, Liping Xu- contributed equally to this work

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Bollig, A., Xu, L., Thakur, A. et al. Regulation of intracellular calcium release and PP1α in a mechanism for 4-hydroxytamoxifen-induced cytotoxicity. Mol Cell Biochem 305, 45–54 (2007). https://doi.org/10.1007/s11010-007-9526-2

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  • DOI: https://doi.org/10.1007/s11010-007-9526-2

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