title: Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway.
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.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul 136-701, Korea.
authors.forename: Jung-A
authors.initials: JA
authors.lastname: Choi
authors.forename: Jin-Wook
authors.initials: JW
authors.lastname: Lee
authors.forename: Hyunju
authors.initials: H
authors.lastname: Kim
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Seo
authors.forename: Jesang
authors.initials: J
authors.lastname: Ko
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000401:mortality*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000502:physiology; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000032:analysis*; D018102:Receptors, Leukotriene B4 / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C485878:LTB4R2 protein, human; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D007975:Leukotriene B4; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C063823:LY 255283