Activation of the Thromboxane A2 Pathway in Human Prostate Cancer Correlates with Tumor Gleason Score and Pathologic Stage

Dassesse, Thibaut; Leval, Xavier de; Leval, Laurence de; Pirotte, Bernard; Castronovo, Vincenzo; Waltregny, David

doi:10.1016/j.eururo.2006.01.036

Cited by 41 publications

(50 citation statements)

References 51 publications

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“…1A, the benign gland (left) showed weak cytoplasmic staining for TP (the stain on luminal surface is likely artifact), whereas the neoplastic glands from the same patient showed strong cytoplasmic staining for TP (right). The clinical relevance of TP expression is also supported by the observations that increased TP expression was associated with extracapsular extension and invasion of the seminal vesicles by prostate tumors (16).…”

Section: Resultssupporting

confidence: 58%

“…Previously, we reported an increase in thromboxane synthase at mRNA level in renal carcinoma, breast carcinoma, prostate cancer, and uterine cancer when compared with their matched normal tissues in a cancer profiling array (15). In prostate cancer, the expression of thromboxane synthase was increased in tumor specimens of advanced stage and grade and particularly in the areas of perineural invasion (15,16). Thromboxane synthase expressed in prostate cancer cells was enzymatically active and may play a contributory role in tumor progression, especially tumor cell motility (15,17,18).…”

Section: Introductionmentioning

confidence: 99%

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Thromboxane A2 Receptors in Prostate Carcinoma: Expression and Its Role in Regulating Cell Motility via Small GTPase Rho

et al. 2008

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Thromboxane A 2 (TxA 2 ) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product prostaglandin H 2 as the substrate. Previously, increased expression of thromboxane synthase was found in prostate tumors, and tumor cell motility was attenuated by inhibitors of thromboxane synthase. This study was undertaken to elucidate how tumor motility is regulated by TxA 2 . Here, we report that human prostate cancer cells express functional receptors for TxA 2 (TP). Ligand binding assay found that PC-3 cells binded to SQ29548, a high-affinity TP antagonist, in a saturable manner with K d of 3.64 nmol/L and B max of 120.4 fmol per million cells. Treatment of PC-3 cells by U46619, a TP agonist, induced PC-3 cell contraction, which was blocked by pretreatment with the TP antagonist SQ29548 or pinane TxA 2 . The migration of prostate cancer cells was significantly inhibited either by sustained activation of TP or by blockade of TP activation, suggesting that TP activation must be tightly controlled during cell migration. Further studies found that small GTPase RhoA was activated by TP activation, and pretreatment of PC-3 cells with Y27632, a Rho kinase (ROCK) inhibitor, blocked U46619-induced cell contraction. A dominant-negative mutant of RhoA also blocked U46619-induced cell contraction. Taken together, the data suggest that TPs are expressed in prostate cancer and activation of TPs regulates prostate cancer cell motility and cytoskeleton reorganization through activation of Rho. [Cancer Res 2008;68(1):115-21]

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Section: Resultssupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Thromboxane A2 Receptors in Prostate Carcinoma: Expression and Its Role in Regulating Cell Motility via Small GTPase Rho

et al. 2008

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“…To date, there have been no studies regarding the significance of Nurr1 expression in human prostate cancer. It is noteworthy that increased levels of thromboxane A2 receptor (TPR) in the prostate cancer were all significantly associated with higher Gleason scores and pathologic stages (Dassesse et al, 2006), moreover, activation of thromboxane A2 receptors may induce Nurr1 expression (Li and Tai, 2009). Therefore, we hypothesized that prostate cancer progression is associated with the level of human Nurr1 protein expression.…”

Section: Orphan Nuclear Receptor Nurr1 As a Potential Novel Marker Fomentioning

confidence: 99%

Orphan Nuclear Receptor Nurr1 as a Potential Novel Marker for Progression in Human Prostate Cancer

Wang¹,

Yang²,

Zou³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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A number of studies have indicated that Nurr1, which belongs to a novel class of orphan nuclear receptors (the NR4A family), is important for carcinogenesis. Here we investigated expression of Nurr1 protein in benign and malignant human prostate tissues and association with clinicopathologic features using immunohistochemical techniques. Moreover, we also investigated the ability of Nurr1 to influence proliferation, migration, invasion and apoptosis of human prostate cancer cells using small interfering RNA silencing. Immunohistochemical analysis revealed that the expression of Nurr1 protein was higher in prostate cancer tissues than in benign prostate tissue (P < 0.001), levels being positively correlated with tumor T classification (P = 0.003), N classification (P = 0.017), M classification (P = 0.011) and the Gleason score (P = 0.020) of prostate cancer patients. In vitro, silencing of endogenous Nurr1 attenuated cell proliferation, migration and invasion, and induced apoptosis of prostate cancer cells. These results suggest that Nurr1 may be used as an indicator for prostate cancer progression and be useful for novel potential therapeutic strategies.

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“…In the prostate, an increased expression of TXS and the TPα/TPβ isoforms directly correlate with the tumour Gleason score and pathologic stage (32,33,47), where expression of both TXS and the TP is mainly found in areas of perineural invasion, a recognized mechanism by which PCa cells invade the prostatic capsule and metastasize to other tissues (20,32). Significantly in the context of PCa, through detailed mechanistic studies, we recently discovered that both the TPα and the TPβ isoforms directly interact with and regulate signalling by protein kinase C-related kinase/ protein kinase novel (PRK/PKN) (48), a family of 3 AGC kinases that act immediately downstream of phosphatidylinositol 3′kinases, and are strongly, yet differentially, implicated in several cancers (49)(50)(51) and in B-cell development (52).…”

Section: The Role Of Thromboxane In Cancermentioning

confidence: 99%

“…Indeed, it has long been known that platelets, the main source of TXA 2 and key target of Aspirin, play a key role in cancer progression promoting cancer cell metastasis, immune evasion and extravasation (30). Furthermore, increased levels of TXA 2 and expression of its synthase and its T prostanoid receptor, the TP, occur in a number of prevalent cancers including, for example, strongly correlating with bladder (31), prostate (32,33), colorectal (34,35) and non-small-cell lung cancer (36). Mechanistically, the role of TXA 2 in neoplastic progression is at least partly explained by the ability of the TXA 2 -TP axis to regulate key mitogenic/ERK-and RhoA-mediated signalling cascades that contribute to tumour development and metastasis (12,14) and also by its ability to regulate local inflammation and immunity (37)(38)(39)(40)(41)(42), including within the tumour (Figure 2; summary of TXA 2 -TP signalling).…”

Section: The Role Of Thromboxane In Cancermentioning

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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Activation of the Thromboxane A2 Pathway in Human Prostate Cancer Correlates with Tumor Gleason Score and Pathologic Stage

Cited by 41 publications

References 51 publications

Thromboxane A2 Receptors in Prostate Carcinoma: Expression and Its Role in Regulating Cell Motility via Small GTPase Rho

Thromboxane A2 Receptors in Prostate Carcinoma: Expression and Its Role in Regulating Cell Motility via Small GTPase Rho

Orphan Nuclear Receptor Nurr1 as a Potential Novel Marker for Progression in Human Prostate Cancer

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

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