Relationship Between Cysteinyl-Leukotriene-1 Receptor and Human Transitional Cell Carcinoma in Bladder

Matsuyama, Masahide; Funao, Kiyoaki; Hayama, Takuma; Tanaka, Tomoaki; Kawahito, Yutaka; Sano, Hajime; Takemoto, Yoshiaki; Nakatani, Tatsuya; Yoshimura, Rikio

doi:10.1016/j.urology.2008.11.005

Cited by 25 publications

(28 citation statements)

References 11 publications

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“…CysLT 1 R has been shown to be upregulated in several types of human cancers, including transitional cell carcinoma (TCC) in the bladder, neuroblastoma, and brain, prostate, breast, and colon cancers [16], [34], [36], [37], [38], [39]. Its increased expression in tumors is also correlated with poor survival in patients with breast or colon cancer [16], [39].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, CysLT 1 R antagonist treatment has been shown to inhibit growth of a series of human urological cancer cell lines (e.g., renal cell carcinoma, bladder cancer, prostate cancer, and testicular cancer) by inducing apoptosis [46]. It has also been shown that administration of Montelukast (100 µM) induces early apoptosis in T24 cells, a human TCC cell line, and in three different prostate cancer cell lines [34], [36]. Montelukast has also been shown to induce the intrinsic apoptotic pathway, resulting in cleavage of caspases 3 and 9, and cell cycle arrest in neuroblastoma cell lines [37].…”

Section: Discussionmentioning

confidence: 99%

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CysLT1R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer

et al. 2013

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The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21WAF/Cip1 (P<0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P<0.01) and reduced vessel size (P<0.05) were also observed, the latter only in the ZM198,615-pretreatment group. Furthermore, we performed a series of in vitro studies using the colon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CysLT1R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer

et al. 2013

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“…Here we show that expression of CysLT 1 R is unaffected by ATRA treatment. High CysLT 1 R expression in cancer patients is not restricted to colorectal cancer cells; it has also been observed in transitional cell carcinoma of the bladder [58], neuroblastoma [59], astrocytoma [60], and in classical Hodgkin’s lymphoma [61]. ATRA’s mechanism of action on cysteinyl leukotriene receptors may also highlight a signaling pathway that contributes to other cancer types.…”

Section: Discussionmentioning

confidence: 99%

The cysteinyl leukotriene 2 receptor contributes to all-transretinoic acid-induced differentiation of colon cancer cells

Bengtsson¹,

Jönsson

Magnusson

et al. 2013

BMC Cancer

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BackgroundCysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT1R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT2R) is lost. Further, our previous data indicate that patients with high CysLT1R and low CysLT2R expression have a poor prognosis. In this study, we examined whether the balance between CysLT1R and CysLT2R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA).MethodsTo determine the effect of ATRA on CysLT2R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions.ResultsATRA treatment induces CysLT2R mRNA and protein expression without affecting CysLT1R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C4 synthase, the enzyme responsible for the production of the ligand for CysLT2R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT2R-specific inhibitor.ConclusionsThis study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway.

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“…The leukotrienes have also been shown to be released by the tissues derived from colon cancer patients [125] . CysLT 1 receptors were also detected in astrocytoma, ganglioglioma and metastatic adenocarcinoma [126,127] . In addition, exposing intestinal epithelial cells in culture to LTD 4 for extended periods causes upregulation of proteins associated with colon carcinogenesis [122] .…”

Section: Cancermentioning

confidence: 95%

Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics

Singh¹,

Gupta²,

Dastidar³

et al. 2010

Pharmacology

186

143

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The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells, eosinophils, basophils and macrophages. The family includes leukotriene C₄ (LTC₄), leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄), which are potent biological mediators in the pathophysiology of inflammatory diseases and trigger contractile and inflammatory processes through the specific interaction with cell surface receptors, belonging to the superfamily of G-protein-coupled receptor. Pharmacological characterizations have suggested the existence of at least 2 types of CysLT receptors based on potency of agonist and antagonist, designated as CysLT₁ and CysLT₂. The CysLT₁ receptors are mostly expressed in lung smooth muscle cells, interstitial lung macrophages and the spleen, and it has been studied a lot elucidating its role in the etiology of airway inflammation and asthma. On the other hand, CysLT₂ receptors are present in the heart, brain and adrenal glands. This review discusses the role of CysLTs and their receptor in the pathophysiology of various inflammatory disorders. The understanding of CysLTs and their receptors in allergic airway disease is currently limited to CysLT₁-receptor-mediated effects, and the role of the CysLT₂ receptors is pharmacologically less well defined, as there is no specific antagonist available yet. Specific CysLT₂-receptor-selective antagonists would be very helpful to identify the precise role of CysLT and their receptors. Some recent evidence indicates the existence of additional receptor subtypes and requires further investigation for a better understanding of the role of the CysLT receptors. This review is an effort to summarize the localization, regulation and expression pattern along with the molecular and functional pharmacology of the CysLT receptors and to discuss their role in the pathophysiology of different diseases along with the recent update.

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Relationship Between Cysteinyl-Leukotriene-1 Receptor and Human Transitional Cell Carcinoma in Bladder

Cited by 25 publications

References 11 publications

CysLT1R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer

CysLT1R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer

The cysteinyl leukotriene 2 receptor contributes to all-transretinoic acid-induced differentiation of colon cancer cells

Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics

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