Research article summary (published 23 Aug 2009):

Restoring endocrine response in breast cancer cells by inhibition of the sphingosine kinase-1 signaling pathway.

Full Abstract

We previously demonstrated that sphingosine kinase-1 (SphK1) is an important mediator in the cytoplasmic signaling of estrogens, including Ca(2+) mobilization, ERK1/2 activation, and the epidermal growth factor receptor transactivation. Here we report for the first time that SphK1 activity is causally associated with endocrine resistance in MCF-7 human breast cancer cells. Enforced overexpression of human SphK1 in MCF-7 cells resulted in enhanced cell proliferation and resistance to tamoxifen-induced cell growth arrest and apoptosis. Tamoxifen-resistant (TamR) MCF-7 cells selected by prolonged exposure to 4-hydroxytamoxifen, exhibited higher levels in SphK1 expression and activity, compared with the control cells. Inhibition of SphK1 activity by either specific pharmaceutical inhibitors or the dominant-negative mutant SphK1(G82D) restored the antiproliferative and proapoptotic effects of tamoxifen in the TamR cells. Furthermore, silencing of SphK1, but not SphK2, expression by the specific small interference RNA also restored the tamoxifen responsiveness in the TamR cells. Thus, blockade of the SphK1 signaling pathway may reprogram cellular responsiveness to tamoxifen and abrogate antiestrogen resistance in human breast cancer cells.

Author information

Author/s: Sukocheva, Olga (O); Wang, Lijun (L); Verrier, Emily (E); Vadas, Mathew A (MA); Xia, Pu (P);

Affiliation: Signal Transduction Laboratory, Centenary Institute, Newtown, New South Wales 2042, Australia.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Endocrinology (Endocrinology), published in United States. (Language: eng)

Reference: 2009-Oct; vol 150 (issue 10) : pp 4484-92

Dates: Created 2009/09/22; Completed 2009/10/22;

PMID: 19706837, status: MEDLINE (last retrieval date: 10/22/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Antineoplastic Agents, Hormonal - pharmacology Breast Neoplasms - enzymology Cell Line, Tumor Drug Resistance, Neoplasm Female

Humans Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; metabolism RNA, Small Interfering - metabolism Signal Transduction Tamoxifen - pharmacology

Associated Chemicals: Antineoplastic Agents, Hormonal (0) ; RNA, Small Interfering (0) ; Tamoxifen (10540-29-1) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-)

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