Role of the BLT2, a leukotriene B4 receptor, in Ras transformation

Min Hyuk Yoo; Haiwon Song; Chang Hoon Woo; Heung Gyu Kim; Jae Hong Kim

doi:10.1038/sj.onc.1208151

Role of the BLT2, a leukotriene B₄ receptor, in Ras transformation

Min Hyuk Yoo, Haiwon Song, Chang Hoon Woo, Heung Gyu Kim, Jae Hong Kim

Division of life Sciences

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

45 Citations (Scopus)

Abstract

Oncogenic Ras is known to drive both the Rac and Raf-MAP-kinase pathways, which act in concert to cause cell transformation. Unlike the Raf-MAP-kinase cascade, however, the downstream elements of Rac pathway are not fully understood. Previously, we showed that cytosolic phospholipase A₂ (cPLA₂) and subsequent metabolism of arachidonic acid act downstream of Rac to mediate the transformation signaling induced by Ha-Ras^V12. In the present study, we observed that leukotriene B₄ (LTB ₄) and its synthetic enzymes as well as BLT2, the low-affinity LTB₄ receptor, are all elevated in Ha-Ras^V12-transformed cells. In addition, the malignant phenotypes of Ras-transformed cells were markedly inhibited by BLT2 blockade, as was their tumorigenicity in vivo. Finally, in situ hybridization analysis revealed that expression of BLT2 is significantly upregulated in a variety of human cancers. Taken together, our results suggest that an LTB₄-BLT2-linked cascade plays a crucial mediatory role in the cell transformation induced by oncogenic Ha-Ras ^V12, possibly acting downstream of Rac-cPLA₂.

Original language	English
Pages (from-to)	9259-9268
Number of pages	10
Journal	Oncogene
Volume	23
Issue number	57
DOIs	https://doi.org/10.1038/sj.onc.1208151
Publication status	Published - 2004 Dec 9

Keywords

BLT2
Cancer
Leukotriene B
Ras transformation

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

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

Access to Document

10.1038/sj.onc.1208151

Cite this

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title = "Role of the BLT2, a leukotriene B4 receptor, in Ras transformation",

abstract = "Oncogenic Ras is known to drive both the Rac and Raf-MAP-kinase pathways, which act in concert to cause cell transformation. Unlike the Raf-MAP-kinase cascade, however, the downstream elements of Rac pathway are not fully understood. Previously, we showed that cytosolic phospholipase A2 (cPLA2) and subsequent metabolism of arachidonic acid act downstream of Rac to mediate the transformation signaling induced by Ha-RasV12. In the present study, we observed that leukotriene B4 (LTB 4) and its synthetic enzymes as well as BLT2, the low-affinity LTB4 receptor, are all elevated in Ha-RasV12-transformed cells. In addition, the malignant phenotypes of Ras-transformed cells were markedly inhibited by BLT2 blockade, as was their tumorigenicity in vivo. Finally, in situ hybridization analysis revealed that expression of BLT2 is significantly upregulated in a variety of human cancers. Taken together, our results suggest that an LTB4-BLT2-linked cascade plays a crucial mediatory role in the cell transformation induced by oncogenic Ha-Ras V12, possibly acting downstream of Rac-cPLA2.",

keywords = "BLT2, Cancer, Leukotriene B, Ras transformation",

author = "Yoo, {Min Hyuk} and Haiwon Song and Woo, {Chang Hoon} and Kim, {Heung Gyu} and Kim, {Jae Hong}",

note = "Funding Information: We would like to thank Dr Takao Shimizu and Dr Takehiko Yokomizo (The University of Tokyo, Tokyo, Japan) for kindly providing BLT expression plasmids and Pfizer Inc. for generously providing the leukotriene B4 receptor inhibitor CP105696. This work was supported by grants from the SRC program (Aging and Apoptosis Research Center) (2002) from the Korea Science and Engineering Foundation (KOSEF), a Molecular and Cellular BioDiscovery Research Program grant (M10311000003-03B4500-00100), and a Frontier 21 Programs (Proteomics; to JH Kim) from the Ministry of Science and Technology, South Korea.",

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AU - Yoo, Min Hyuk

AU - Song, Haiwon

AU - Woo, Chang Hoon

AU - Kim, Heung Gyu

AU - Kim, Jae Hong

N1 - Funding Information: We would like to thank Dr Takao Shimizu and Dr Takehiko Yokomizo (The University of Tokyo, Tokyo, Japan) for kindly providing BLT expression plasmids and Pfizer Inc. for generously providing the leukotriene B4 receptor inhibitor CP105696. This work was supported by grants from the SRC program (Aging and Apoptosis Research Center) (2002) from the Korea Science and Engineering Foundation (KOSEF), a Molecular and Cellular BioDiscovery Research Program grant (M10311000003-03B4500-00100), and a Frontier 21 Programs (Proteomics; to JH Kim) from the Ministry of Science and Technology, South Korea.

PY - 2004/12/9

Y1 - 2004/12/9

N2 - Oncogenic Ras is known to drive both the Rac and Raf-MAP-kinase pathways, which act in concert to cause cell transformation. Unlike the Raf-MAP-kinase cascade, however, the downstream elements of Rac pathway are not fully understood. Previously, we showed that cytosolic phospholipase A2 (cPLA2) and subsequent metabolism of arachidonic acid act downstream of Rac to mediate the transformation signaling induced by Ha-RasV12. In the present study, we observed that leukotriene B4 (LTB 4) and its synthetic enzymes as well as BLT2, the low-affinity LTB4 receptor, are all elevated in Ha-RasV12-transformed cells. In addition, the malignant phenotypes of Ras-transformed cells were markedly inhibited by BLT2 blockade, as was their tumorigenicity in vivo. Finally, in situ hybridization analysis revealed that expression of BLT2 is significantly upregulated in a variety of human cancers. Taken together, our results suggest that an LTB4-BLT2-linked cascade plays a crucial mediatory role in the cell transformation induced by oncogenic Ha-Ras V12, possibly acting downstream of Rac-cPLA2.

AB - Oncogenic Ras is known to drive both the Rac and Raf-MAP-kinase pathways, which act in concert to cause cell transformation. Unlike the Raf-MAP-kinase cascade, however, the downstream elements of Rac pathway are not fully understood. Previously, we showed that cytosolic phospholipase A2 (cPLA2) and subsequent metabolism of arachidonic acid act downstream of Rac to mediate the transformation signaling induced by Ha-RasV12. In the present study, we observed that leukotriene B4 (LTB 4) and its synthetic enzymes as well as BLT2, the low-affinity LTB4 receptor, are all elevated in Ha-RasV12-transformed cells. In addition, the malignant phenotypes of Ras-transformed cells were markedly inhibited by BLT2 blockade, as was their tumorigenicity in vivo. Finally, in situ hybridization analysis revealed that expression of BLT2 is significantly upregulated in a variety of human cancers. Taken together, our results suggest that an LTB4-BLT2-linked cascade plays a crucial mediatory role in the cell transformation induced by oncogenic Ha-Ras V12, possibly acting downstream of Rac-cPLA2.

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