Reactive oxygen species are generated through a BLT2-linked cascade in Ras-transformed cells.
Although production of reactive oxygen species (ROS) by oncogenic Ras is thought to be crucial for Ras transformation, very little is known about the signaling mechanism involved. In the present study, we investigated whether BLT2, a low-affinity leukotriene B(4) receptor, is involved in the generation of ROS in H-Ras(V12)-transformed fibroblasts. We show that downregulation of BLT2 using RNA interference or antisense oligonucleotides inhibits ROS generation, and that Nox1 acts downstream of BLT2. Moreover, BLT2 overexpression caused increased ROS production and partial transformation. Taken together, our results suggest that a BLT2-Nox1-linked cascade is responsible for the elevated ROS generation in Ras-transformed cells. Our finding may contribute to clarifying the signaling events underlying the enhanced levels of ROS frequently observed in various transformed cells and possibly serve as a basis for developing new therapeutic strategies for human cancers.
Choi
Jung-A
JA
School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul, 136-701, Korea.
Kim
Eun-Young
EY
Song
Haiwon
H
Kim
Cheolmin
C
Kim
Jae-Hong
JH
D000818:Animals; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D007975:Leukotriene B4 / Q000502:physiology; D009247:NADH, NADPH Oxidoreductases / Q000502:physiology; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000502:physiology; D009861:Onium Compounds / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000502:physiology*; D014162:Transfection
C485878:LTB4R2 protein, human; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; C007517:diphenyleneiodonium; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C000614712:NOX1 protein, rat