Ras-induced invasion and metastasis are regulated by a leukotriene B 4 receptor BLT2-linked pathway

E. Y. Kim; J. M. Seo; K. J. Cho; J. H. Kim

doi:10.1038/onc.2009.412

Ras-induced invasion and metastasis are regulated by a leukotriene B 4 receptor BLT2-linked pathway

E. Y. Kim
, J. M. Seo
, K. J. Cho
, J. H. Kim^*

^*Corresponding author for this work

Division of life Sciences

Research output: Contribution to journal › Article › peer-review

47 Citations (Scopus)

Abstract

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-B 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.

Original language	English
Pages (from-to)	1167-1178
Number of pages	12
Journal	Oncogene
Volume	29
Issue number	8
DOIs	https://doi.org/10.1038/onc.2009.412
Publication status	Published - 2010 Feb

Bibliographical note

Funding Information:
We thank Dr Takao Shimizu (University of Tokyo, Tokyo, Japan) and Dr Takehiko Yokomizo (University of Kyushu, Fukuoka, Japan) for the BLT2 expression plasmids. This work was supported by the Diseases Network Research Program (M10751050001-08N5105-00110), and the SRC-Aging and Apoptosis Research program (20090062880) from the Ministry of Education, Science, and Technology, Korea.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

H-Ras
Leukotriene B receptor BLT2
MMP-9
Metastasis
ROS

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

Access to Document

10.1038/onc.2009.412

Cite this

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title = "Ras-induced invasion and metastasis are regulated by a leukotriene B 4 receptor BLT2-linked pathway",

abstract = "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-B 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.",

keywords = "H-Ras, Leukotriene B receptor BLT2, MMP-9, Metastasis, ROS",

author = "Kim, \{E. Y.\} and Seo, \{J. M.\} and Cho, \{K. J.\} and Kim, \{J. H.\}",

note = "Funding Information: We thank Dr Takao Shimizu (University of Tokyo, Tokyo, Japan) and Dr Takehiko Yokomizo (University of Kyushu, Fukuoka, Japan) for the BLT2 expression plasmids. This work was supported by the Diseases Network Research Program (M10751050001-08N5105-00110), and the SRC-Aging and Apoptosis Research program (20090062880) from the Ministry of Education, Science, and Technology, Korea.",

year = "2010",

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doi = "10.1038/onc.2009.412",

language = "English",

volume = "29",

pages = "1167--1178",

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AU - Kim, E. Y.

AU - Seo, J. M.

AU - Cho, K. J.

AU - Kim, J. H.

N1 - Funding Information: We thank Dr Takao Shimizu (University of Tokyo, Tokyo, Japan) and Dr Takehiko Yokomizo (University of Kyushu, Fukuoka, Japan) for the BLT2 expression plasmids. This work was supported by the Diseases Network Research Program (M10751050001-08N5105-00110), and the SRC-Aging and Apoptosis Research program (20090062880) from the Ministry of Education, Science, and Technology, Korea.

PY - 2010/2

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N2 - 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-B 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.

AB - 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-B 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.

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KW - Leukotriene B receptor BLT2

KW - MMP-9

KW - Metastasis

KW - ROS

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AN - SCOPUS:77649184896

SN - 0950-9232

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JO - Oncogene

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IS - 8

ER -

Ras-induced invasion and metastasis are regulated by a leukotriene B 4 receptor BLT2-linked pathway

Abstract

Bibliographical note

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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