TY - JOUR
T1 - Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway
AU - Choi, Jung A.
AU - Lee, Jin Wook
AU - Kim, Hyunju
AU - Kim, Eun Young
AU - Seo, Ji Min
AU - Ko, Jesang
AU - Kim, Jae Hong
N1 - 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).
PY - 2009/9/11
Y1 - 2009/9/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77950878441&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgp203
DO - 10.1093/carcin/bgp203
M3 - Article
C2 - 19748928
AN - SCOPUS:77950878441
SN - 0143-3334
VL - 31
SP - 543
EP - 551
JO - Carcinogenesis
JF - Carcinogenesis
IS - 4
ER -