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 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.
Highlights
Bladder cancer is the second most common genitourinary malignant disease and the number of diagnosed cases is increasing annually in the United States (Jemal et al, 2008)
Both BLT2 and its ligands appear to be upregulated in bladder cancer cells and suggest a potential role of BLT2 signalling in bladder cancer progression
When cells were treated with LY255283 for 48 h, we observed significant DNA ladder formation, which is a characteristic of apoptosis (Figure 1F), together suggesting that BLT2 is somehow necessary for bladder cancer cell survival
Summary
Bladder cancer is the second most common genitourinary malignant disease and the number of diagnosed cases is increasing annually in the United States (Jemal et al, 2008). 90% of malignant tumors arising in the urinary bladder are epithelial origin, the majority being transitional cell carcinomas (TCCs). Of all newly diagnosed cases of TCCs, about 70% present as superficial tumor (stages Tis, Ta, and T1), but as many as 50-70% of those superficial tumor will recur and 10-20% will progress to more invasive and aggressive tumor (stages T2-4). Recent studies have revealed potential roles of the 5-, 12-, and 15-lipoxygenase (LO) pathways in cancer progression. In accordance with the suggested role of 12-LO in cancer, 12(S)-hydroxyeicosatetraenoic acid (12(S)HETE), a 12-LO pathway metabolite, was shown to influence tumor progression (Nie et al, 2006). Leukotriene B4 (LTB4), one of the 5-LO pathway metabolites, was recently shown to stimulate cell proliferation via ERK signalling pathways in several types of cancer cells, including pancreatic
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