Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway.
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.
Choi
Jung-A
JA
School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul 136-701, Korea.
Lee
Jin-Wook
JW
Kim
Hyunju
H
Kim
Eun-Young
EY
Seo
Ji-Min
JM
Ko
Jesang
J
Kim
Jae-Hong
JH
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
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