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

Oncogene volume 23, pages 9259–9268 (2004)Cite this article

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 (LTB4) 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-RasV12, possibly acting downstream of Rac-cPLA2.

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Acknowledgements

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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  1. School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul, 136-701, Korea

    Min-Hyuk Yoo, Haiwon Song, Chang-Hoon Woo, HeungGyu Kim & Jae-Hong Kim

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Correspondence to Jae-Hong Kim.

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Yoo, MH., Song, H., Woo, CH. et al. Role of the BLT2, a leukotriene B4 receptor, in Ras transformation. Oncogene 23, 9259–9268 (2004). https://doi.org/10.1038/sj.onc.1208151

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