Exp Mol Med.  2011 Mar;43(3):129-137. 10.3858/emm.2011.43.3.014.

Up-regulation of BLT2 is critical for the survival of bladder cancer cells

• Seo JM
• Cho KJ
• Kim EY
• Choi MH
• Chung BC
• Kim JH

• KMID: 1109401
• DOI: http://doi.org/10.3858/emm.2011.43.3.014

Abstract

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 B4 (LTB4) 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.

Keyword

biological markers; cell survival; LTB4R2 protein, human; NADPH oxidase; reactive oxygen species; urinary bladder neoplasms

MeSH Terms

*Apoptosis
Blotting, Western
Cell Proliferation
Cells, Cultured
Gene Expression Regulation, Neoplastic/*physiology
Humans
Leukotriene Antagonists/pharmacology
NADPH Oxidase/antagonists & inhibitors/genetics/metabolism
Phosphorylation
RNA, Messenger/genetics
RNA, Small Interfering/genetics
Reactive Oxygen Species/*metabolism
Receptors, Leukotriene B4/antagonists & inhibitors/*genetics
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Tetrazoles/pharmacology
Up-Regulation
Urinary Bladder Neoplasms/*genetics/mortality