Up-regulation of BLT2 is critical for the survival of bladder cancer cells.
The incidence rates of urinary bladder cancer continue to rise yearly, and thus new therapeutic approaches and early diagnostic markers for bladder cancer are urgently needed. Thus, identifying the key mediators and molecular mechanisms responsible for the survival of bladder cancer has valuable implications for the development of therapy. In this study, the role of BLT2, a receptor for leukotriene B((4)) (LTB((4))) and 12(S)-hydroxyeicosatetraenoic acid (HETE), in the survival of bladder cancer 253J-BV cells was investigated. We found that the expression of BLT2 is highly elevated in bladder cancer cells. Also, we observed that blockade of BLT2 with an antagonist or BLT2 siRNA resulted in cell cycle arrest and apoptotic cell death, suggesting a role of BLT2 in the survival of human bladder cancer 253J-BV cells. Further experiments aimed at elucidating the mechanism by which BLT2 mediates survival revealed that enhanced level of reactive oxygen species (ROS) are generated via a BLT2-dependent up-regulation of NADPH oxidase members NOX1 and NOX4. Additionally, we observed that inhibition of ROS generation by either NOX1/4 siRNAs or treatment with an ROS-scavenging agent results in apoptotic cell death in 253J-BV bladder cancer cells. These results demonstrated that a 'BLT2-NOX1/4-ROS' cascade plays a role in the survival of this aggressive bladder cancer cells, thus pointing to BLT2 as a potential target for anti-bladder cancer therapy.
School of Life Sciences and Biotechnology Korea University, Seoul, Korea.
Ji Min
JM
Seo
Kyung Jin
KJ
Cho
Eun Young
EY
Kim
Man Ho
MH
Choi
Bong Chul
BC
Chung
Jae Hong
JH
Kim
D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality
C485878:LTB4R2 protein, human; D020024:Leukotriene Antagonists; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human; C063823:LY 255283
Reprod Sci. 2008 Apr;15(3):321-6
18421027
Leukemia. 2005 Nov;19(11):1977-84
16151469
Biochem Biophys Res Commun. 2005 Sep 30;335(3):949-56
16105664
Cancer Metastasis Rev. 2006 Dec;25(4):695-705
17160708
J Urol. 2003 Nov;170(5):1994-9
14532840
Carcinogenesis. 2010 Apr;31(4):543-51
19748928
Lancet. 2009 Jul 18;374(9685):239-49
19520422
Br J Cancer. 2008 Oct 7;99(7):1064-73
18781173
CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
18287387
Prostaglandins Leukot Essent Fatty Acids. 2003 Aug-Sep;69(2-3):123-34
12895595
Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):915-20
19286633
Free Radic Biol Med. 2009 Jan 1;46(1):42-50
18930813
Free Radic Biol Med. 2008 Feb 15;44(4):624-34
18082638
Mol Cell Biol. 2004 May;24(10):4384-94
15121857
J Biol Chem. 2007 Aug 17;282(33):24364-72
17573344
Int J Urol. 2006 Aug;13(8):1086-91
16903934
Free Radic Biol Med. 2010 Sep 15;49(6):1072-81
20600831
J Biol Chem. 2002 Mar 8;277(10):8572-8
11756405
Oncogene. 2003 Sep 4;22(38):6045-53
12955083
Oncogene. 2006 Jun 22;25(26):3699-707
16532036
Antioxid Redox Signal. 2008 Aug;10(8):1343-74
18522489
J Cell Sci. 2008 Apr 15;121(Pt 8):1183-92
18349077
Oncogene. 2010 Feb 25;29(8):1167-78
19935719
Anticancer Drugs. 2007 Jun;18(5):535-41
17414622
Scand J Urol Nephrol Suppl. 2008 Sep;(218):154-65
18815930
J Biol Chem. 2006 Jul 7;281(27):18601-9
16638750
Gastroenterology. 2007 Nov;133(5):1637-48
17983808
Cancer Lett. 2004 Jul 8;210(1):41-6
15172119