Novel Role of Thromboxane Receptors β Isoform in Bladder Cancer Pathogenesis

Moussa, Omar; Ashton, Anthony W.; Fraig, Mostafa; Garrett‐Mayer, Elizabeth; Ghoneim, Mohamed A.; Halushka, Perry V.; Watson, Dennis K.

doi:10.1158/0008-5472.can-07-6560

Cited by 57 publications

(76 citation statements)

References 40 publications

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“…to an increase in apoptosis regardless of cell type, which is supported by the previous reports showing that inhibition of TxAS resulted in apoptosis in bladder (Moussa et al, 2008a) and lung (Cathcart et al, 2010) cancer cells, and that treatment with TxA 2 receptor antagonists also caused significant apoptosis in bladder cancer cells (Moussa et al, 2008b).…”

Section: Discussionsupporting

confidence: 82%

“…For example, it has recently been demonstrated that the activation of TxA 2 receptor by I-BOP (another TxA 2 mimetic) promoted cell proliferation in lung A549 (NSCLC) cells (Li and Tai, 2009). In addition, the bladder cancer cells transfected with b-isoform of TxA 2 receptor and stimulated with U46619 resulted in a significant increase in cellular growth rate and PCNA expression (Moussa et al, 2008b). A recent study has also reported that treatment of two NSCLC cell lines with another selective TxAS inhibitor ozagrel induced a significant reduction in cell proliferation (Cathcart et al, 2010).…”

Section: Discussionmentioning

confidence: 95%

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4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

Huang

Hsin

et al. 2010

Oncogene

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The role of thromboxane A 2 (TxA 2 ) in smokingassociated lung cancer is poorly understood. This study was conducted to study the role of TxA 2 in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA 2 synthase (TxAS) expression and thromboxane B 2 (TxB 2 ) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA 2 receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA 2 receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA 2 receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA 2 synthesis and activates its receptor in lung cancer cells. The increased TxA 2 may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 95%

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

Huang

Hsin

et al. 2010

Oncogene

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“…Here, we showed that NS398, SQ29548, and TP silencing induced apoptosis in two MM cell lines, and U46619 protected MM cells from apoptosis. These findings were consistent with previous data from other cell types (7,49,50). Meanwhile, we found that NS398, SQ29548, and TP silencing elevated caspase 3 activity, and, as expected, U46619 decreased caspase 3 activity, in accordance with flow cytometry results.…”

Section: Discussionsupporting

confidence: 93%

Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis

Liu

Tao

Liu

et al. 2016

Journal of Biological Chemistry

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Multiple myeloma (MM) is a plasma cell malignancy without effective therapeutics. Thromboxane A 2 (TxA 2 )/TxA 2 receptor (T prostanoid receptor (TP)) modulates the progression of some carcinomas; however, its effects on MM cell proliferation remain unclear. In this study, we evaluated cyclooxygenase (COX) enzymes and downstream prostaglandin profiles in human myeloma cell lines RPMI-8226 and U-266 and analyzed the effects of COX-1/-2 inhibitors SC-560 and NS-398 on MM cell proliferation. Our observations implicate COX-2 as being involved in modulating cell proliferation. We further incubated MM cells with prostaglandin receptor antagonists or agonists and found that only the TP antagonist, SQ29548, suppressed MM cell proliferation. TP silencing and the TP agonist, U46619, further confirmed this finding. Moreover, SQ29548 and TP silencing promoted MM cell G 2 /M phase delay accompanied by reducing cyclin B1/cyclin-dependent kinase-1 (CDK1) mRNA and protein expression. Notably, cyclin B1 overexpression rescued MM cells from G 2 /M arrest. We also found that the TP agonist activated JNK and p38 MAPK phosphorylation, and inhibitors of JNK and p38 MAPK depressed U46619-induced proliferation and cyclin B1/CDK1 protein expression. In addition, SQ29548 and TP silencing led to the MM cell apoptotic rate increasing with improving caspase 3 activity. The knockdown of caspase 3 reversed the apoptotic rate. Taken together, our results suggest that TxA 2 /TP promotes MM cell proliferation by reducing cell delay at G 2 /M phase via elevating p38 MAPK/JNK-mediated cyclin B1/CDK1 expression and hindering cell apoptosis. The TP inhibitor has potential as a novel agent to target kinase cascades for MM therapy. Multiple myeloma (MM)3 is a B-cell malignancy characterized by the clonal proliferation of neoplastic plasma cells in the bone marrow (BM). It accounts for 12% of all malignant hematological neoplasms and is the second most frequent hematological malignancy (1). Recently, despite the improved therapeutic effect of newly approved chemotherapeutics, including thalidomide, lenalidomide, and bortezomib, and stem cell transplantation, MM remains incurable, with only a marginal increase in the 5-year relative survival rate and a high incidence of relapse (2, 3). Thus, identification of novel therapeutic targets for MM is urgently needed.Growing evidence demonstrates that thromboxane A 2 (TxA 2 )-related molecules are actively involved in tumor progression (4, 5). TxA 2 is one of the five primary prostaglandins (PGs) generated from arachidonic acid (AA) through the cyclooxygenases (COX-1 and COX-2) and TxA 2 synthase pathways and exerts its biological activities through the TxA 2 receptor (T prostanoid receptor (TP)) located on the cell surface. TP belongs to the G-protein-coupled receptor superfamily and is expressed as two isoforms in humans, named TP ␣ and TP ␤ (6). Notably, TxA 2 stimulates proliferation of several types of cells, including oligodendrocytes (7), smooth muscle cells (8), and lung cancer cells (9). For example, ...

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“…As the TXA 2 -TP axis has been implicated in the development of prostate and breast cancer (20,33,47,94,95), the findings herein suggest that aberrant WT1 regulation of TPα expression may contribute to such cancers and potentially to WT itself. In addition, bearing in mind that the TPα and TPβ isoforms display a number of important functional similarities but also differences in terms of their signalling (6) and regulation including in certain cancers (96,97), coupled with the fact that they are regulated by distinct promoters within the TBXA2R gene, it will be of considerable interest to investigate the expression and transcriptional regulation of TPβ in human cancers, in particular in prostate and breast cancer.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

Kinsella

2016

Wilms Tumor

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Copyright: The Author.Licence: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the author and the publisher are explicitly identified and properly acknowledged as the original source. AbstractThe prostanoid thromboxane (TX)A 2 plays a fundamental role in vascular haemostasis and, more recently, is increasingly implicated in various neoplasms including in prostate, breast and bladder cancers, among others. In humans, TXA 2 signals through the TPα and TPβ isoforms of the T prostanoid receptor (TP), two structurally related receptors that display both common, over-lapping but also distinct, isoform-specific physiologic roles. Consistent with this, while TPα and TPβ are encoded by the same gene, the TBXA2R, they are Kinsella 164 differentially expressed due to their transcriptional regulation by distinct promoters where promoter (Prm) 1 regulates TPα expression and Prm3 regulates TPβ. While the clinical evidence for the role of the TXA 2 -TP axis in neoplastic progression is increasing, few studies to date have investigated the role of the individual TPα/TPβ isoforms in human cancer or indeed in most other diseases in which the TXA 2 -TP axis is implicated. Focusing on TPα, this review details the current understanding of the factors regulating its expression and transcriptional regulation through Prm1, including in prostate and breast cancers. Emphasis is placed on the trans-acting transcriptional regulators that bind to cis-elements within the core and upstream regulatory regions of Prm1 under basal conditions and in response to cellular differentiation. A particular focus is placed on the role of the tumour suppressor Wilms' tumour 1 in the regulation of TPα expression through Prm1 in megakaryoblastic cells of vascular origin and in prostate and breast carcinoma cells. Collectively, this review details current knowledge of the factors determining regulation of the TXA 2 -TPα axis and thereby provides a genetic basis for understanding the role of TXA 2 in the progression of certain human cancers.

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Novel Role of Thromboxane Receptors β Isoform in Bladder Cancer Pathogenesis

Cited by 57 publications

References 40 publications

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

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