Prostanoid receptor expression in colorectal cancer related to tumor stage, differentiation and progression

Tao

Journal of Biological Chemistry

et al. 2016

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, ...

mentioning

confidence: 72%

“…Accordingly, TP expression is increased in many tumor tissues compared with non-tumor tissues (11). Moreover, several studies suggest that TP is involved in tumor cell proliferation, migration, and invasion, which are key steps in tumor progression (5).…”

Section: Discussionmentioning

confidence: 99%

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

Tao

Journal of Biological Chemistry

et al. 2016

“…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

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.

“…Our previous investigations have indicated that expression of COX-2 and subtype EP 2 receptors in colorectal cancer tissue predict patient survival following intended curative operation (3). Thus, prostaglandins are involved in different metabolic pathways assumed to support tumor progression by alterations in cell proliferation, adhesion, migration, differentiation, apoptosis and angiogenesis (1,2,(4)(5)(6)(7)(8)(9)(10)(11). The main function of NSAIDs is reversible inhibition of COX enzymes, where COX-1 is constitutively expressed in most tissues, while COX-2 is usually induced by growth factors and cytokines (12).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, cyclooxygenases are key enzymes in prostaglandin biosynthesis for conversion of arachidonic acid to the prostaglandin (PG) precursor PGH 2 , which is immediately converted to different prostaglandins (PGH 2 , PGE 2 , PGH 2· , PGI 2 /prostacyclin or TXA 2 ) depending on various cellular enzyme synthases (15). Net effects of COX enzymes in tumor tissue and cells depend on the balance between produced prostaglandins and interactions with corresponding receptors (3,11,(16)(17)(18). Enzymes catalyzing degradation of prostaglandins as 15-hydroxyprostaglandin dehydrogenase (HPGD) should also be of importance for overall tissue levels of PGE 2 (19), although less evaluated in relationship to tumor progression (12).…”

Section: Introductionmentioning

confidence: 99%

Receptor and enzyme expression for prostanoid metabolism in colorectal cancer related to tumor tissue PGE2

Gustafsson

Andersson²,

Lagerstedt³

et al. 2009

Int J Oncol

Abstract. Prostaglandins support progression of colorectal cancer by several mechanisms. This conclusion is based on epidemiological and drug intervention long-term studies or retrieved from animal and cell culture experiments. The aim of the present study was to map receptor and enzyme expression for prostanoid metabolism in the presence of high or low PGE 2 content within colon cancer tissue at primary tumor operation and after short-term preoperative provision of non-steroidal anti-inflammatory drug (NSAID). Twentythree unselected patients with colon cancer were randomly selected to receive indomethacin (NSAID) or sham treatment for 3 days before surgery. Normal colon and tumor tissue were collected at operation for RNA extraction. Tissue PGE 2 levels were measured by radioimmunoassay. Gene expression was quantified by microarray and real-time PCR. COX-1 expression increased proportionally to COX-2 expression in colon cancer tissue from untreated patients. Indomethacin reduced PGE 2 content in normal and tumor tissue with subsequently decreased IP, HPGD and PPARÁ receptor expression in both tumor and normal colon tissue, while subtype EP 1-4 receptors were not significantly influenced by indomethacin treatment. MPGES-1 expression was not related to overall PGE 2 content in tumor and colon tissue, but decreased significantly in normal tissue during indomethacin exposure. Reduction of tumor tissue PGE 2 was related to significant alteration in expression of several hundred genes indicating decreased cell cycling and increased apoptosis during indomethacin treatment, probably related to upregulation of acute phase reactants in tumor tissue. Increased prostanoid activity in colon cancer tissue is related to cross-talk between tumor and stroma cells.