Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway.
Ras signaling pathways are well-recognized for their involvement in cancer cell proliferation; however, considerably less is known regarding their contribution to invasion and metastasis. Here, we demonstrate that a novel BLT2, a low-affinity leukotriene B(4) receptor-linked signaling cascade involving the generation of reactive oxygen species (ROS) via Nox1, NF-kappaB stimulation and subsequent upregulation of matrix metalloproteinase-9 (MMP-9) is a potential mechanism by which Ras promotes invasion and metastasis. We found that inhibition of BLT2 signaling markedly suppressed Ras-evoked metastasis and reduced the associated mortality in mice. Consistent with the proposed role of BLT2 as a key downstream mediator of Ras signaling to metastasis, BLT2 expression alone resulted in the formation of numerous metastatic lung nodules and the nodules formation was significantly attenuated by the inhibition of MMP-9, a downstream component of BLT2. Together, our results reveal the previously unsuspected function of BLT2-linked cascade in driving oncogenic Ras-induced metastasis and would provide a valuable insight into invasion and metastasis.
Kim
E-Y
EY
Inflammatory Signaling Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Seo
J-M
JM
Cho
K-J
KJ
Kim
J-H
JH
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D007975:Leukotriene B4 / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009369:Neoplasms / Q000473:pathology; D009389:Neovascularization, Pathologic; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000819:agonists / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects*; D018631:ras Proteins / Q000502:physiology*
D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins