Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway

Jung A. Choi, Jin Wook Lee, Hyunju Kim, Eun Young Kim, Ji Min Seo, Jesang Ko, Jae Hong Kim

    Research output: Contribution to journalArticlepeer-review

    50 Citations (Scopus)

    Abstract

    Leukotriene B4 (LTB4) is an inflammatory mediator with potent biological activities in the pathogenesis of many inflammatory diseases. In the present study, we found that expression of BLT2, a low-affinity LTB4 receptor, is significantly upregulated in breast cancer cells. In addition, we observed that inhibition of BLT2 by a specific antagonist, LY255283, or by siBLT2 RNA interference caused dramatic apoptotic cell death in breast cancer cells, especially in the estrogen receptor (ER)-negative MDA-MB-468 and MDA-MB-453 cells, suggesting a role for BLT2 in survival of these breast cancer cells. In an approach to understand the downstream mechanism by which BLT2 mediates the potential pro-survival signaling, we found that the elevated reactive oxygen species (ROS) generation is associated with BLT2-mediated survival. Expression of Nox1, a member of the NADPH oxidase family, is also highly upregulated in a BLT2-dependent manner in these breast cancer cells, suggesting that 'Nox1-derived ROS' lie downstream of BLT2. Consistent with the proposed role of 'Nox1-ROS' in pro-survival signaling, knockdown of Nox1 with siNox1 or treatment with a ROS scavenging agent caused dramatic apoptotic death in these breast cancer cells. Taken together, our results demonstrate, for the first time, that the 'BLT2-Nox1-ROS'-linked cascade is involved in the pro-survival signaling, especially in ER-negative breast cancer cells.

    Original languageEnglish
    Pages (from-to)543-551
    Number of pages9
    JournalCarcinogenesis
    Volume31
    Issue number4
    DOIs
    Publication statusPublished - 2009 Sept 11

    Bibliographical note

    Funding Information:
    Korea Science and Engineering Foundation through the Diseases Network Research Program (M10751050001-08N5105-00110); SRC program funded by the Ministry of Science and Technology, Republic of Korea (Aging and Apoptosis Research Center, 20090062880).

    ASJC Scopus subject areas

    • Cancer Research

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