Regulated expression of the TPβ isoform of the human T prostanoid receptor by the tumour suppressors FOXP1 and NKX3.1: Implications for the role of thromboxane in prostate cancer

O’Sullivan, Aine G.; Eivers, Sarah B.; Mulvaney, Eamon P.; Kinsella, B. Thérèse

doi:10.1016/j.bbadis.2017.09.005

Cited by 7 publications

(18 citation statements)

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“…Hence, imbalances in the levels of TXA 2 , or of TXA 2 S or of the TP have been implicated in a range of cardiovascular, renal and pulmonary diseases, including in PAH [2][3][4][5]. The TXA 2 -TP axis also regulates key mitogenic/ERK and RhoA-mediated signalling cascades, explaining, at least in part, the role of TXA 2 in increasing cell proliferation and migration such as occurs in restenosis, vascular remodelling, and in a range of cancers in which the TXA 2 -TP axis is increasingly implicated [2][3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

et al. 2020

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Background: NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A 2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F 2α , a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs. Methods: PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar-Kyoto rats. Animals were assigned into groups: 1. 'No MCT'; 2. 'MCT Only'; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT. Results: From haemodynamic assessments, NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standardof-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals.

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Section: Introductionmentioning

confidence: 99%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

et al. 2020

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“…The plasmids pGL3B:Prm3 FOXP1*(-1298) , pGL3B:Prm3 FOXP1*(-943) , pGL3B:Prm3 FOXP1*(-597) and pGL3B:Prm3 FOXP1* (-496) were generated by QuikChange TM site-directed mutagenesis (SDM) of the consensus FOXP1 binding site (g/tTGTTg/t to g/tTCCTg/t,) at nucleotide -1298 (FOXP1 #1 ), -943 (FOXP1 #2 ), -597 (FOXP1 #3 ) and -496 (FOXP1 #4 ), respectively, within Prm3, as previously described [33]. In all cases,designation indicates nucleotides 5′ of the translational ATG start codon (designated +1), where the nucleotides that were mutated are underlined in bold.…”

Section: Luciferase-based Genetic Reporter Plasmidsmentioning

confidence: 99%

“…Moreover, in terms of their transcriptional regulation, the Wilms' tumour (WT) 1 and hypermethylated in cancer (HIC) were identified as key transcription factors that regulate TPα expression through Prm1 in the prostate adenocarcinoma PC-3 and LNCaP cell lines [32]. On the other hand, FOXP1 and NKX3.1, two tumour suppressor gene (TSG) products strongly implicated in PCa development, were identified as the key transcription factors regulating TPβ expression through Prm3 in the PCa setting [33].…”

Section: Introductionmentioning

confidence: 99%

“…FOXP1 is a tumour suppressor gene product implicated not only in prostate cancer (PCa) development but also acts as an essential regulator of monocyte-to-macrophage cell differentiation [43,44]. Hence, in view of recent findings that expression of TPβ in PCa is transcriptionally regulated by FOXP1 [33], the current study also explored the intriguing possibility that FOXP1 might play an additional role in the transcriptional regulation of TPβ within the monocytic THP-1 lineage, accounting for the prominent histological expression of TPβ in the tissue resident macrophage in the inflammatory infiltrates of the benign and tumour prostate specimens.…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of the TPα and TPβ isoforms of the human T Prostanoid receptor during chronic inflammation of the prostate: Role for FOXP1 in the transcriptional regulation of TPβ during monocyte-macrophage differentiation

Mulvaney

O’Sullivan

Eivers

et al. 2019

Experimental and Molecular Pathology

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Research highlights:•TPα and TPβ isoforms differentially upregulated in prostate inflammatory infiltrates •TPβ found in 94% of infiltrates, including in B-& T-lymphocytes and in macrophages •TP found in 72% of infiltrates, but expression is mainly confined to macrophages •TPα and TPβ upregulated after monocyte-to macrophage differentiation of THP-1 cells •Tumour suppressor FOXP1 transcriptionally regulates TPβ expression in macrophages AbstractInflammation is linked to prostate cancer (PCa) and to other diseases of the prostate. The prostanoid thromboxane (TX)A2 is a pro-inflammatory mediator implicated in several prostatic diseases, including PCa. TXA2 signals through the TPα and TPβ isoforms of the T Prostanoid receptor (TP) which exhibit several functional differences and transcriptionally regulated by distinct promoters Prm1 and Prm3, respectively, within the TBXA2R gene. This study examined the expression of TPα and TPβ in inflammatory infiltrates within human prostate tissue. Strikingly, TPβ expression was detected in 94% of infiltrates, including in B-and T-lymphocytes and macrophages. In contrast, TPα was more variably expressed and, where present, expression was mainly confined to macrophages. To gain molecular insight into these findings, expression of TPα and TPβ was evaluated as a function of monocyte-tomacrophage differentiation in THP-1 cells. Expression of both TPα and TPβ was upregulated following phorbol-12-myristate-13-acetate (PMA)-induced differentiation of monocytic THP-1 to their macrophage lineage. Furthermore, FOXP1, an essential transcriptional regulator down-regulated during monocyte-to-macrophage differentiation, was identified as a key trans-acting factor regulating TPβ expression through Prm3 in THP-1 cells. Knockdown of FOXP1 increased TPβ, but not TPα, expression in THP-1 cells, while genetic reporter and chromatin immunoprecipitation (ChIP) analyses established that FOXP1 exerts its repressive effect on TPβ through binding to four cis-elements within Prm3. Collectively, FOXP1 functions as a transcriptional repressor of TPβ in monocytes. This repression is lifted in differentiated macrophages, allowing for upregulation of TPβ expression and possibly accounting for the prominent expression of TPβ in prostate tissue-resident macrophages.

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“…(2)(3)(4)(5) The TXA 2 -TP axis also regulates key mitogenic/ERK and RhoA-mediated signalling cascades, explaining, at least in part, the role of TXA 2 in increasing cell proliferation and migration such as occurs in restenosis, vascular remodelling, and in a range of cancers in which the TXA 2 -TP axis is increasingly implicated. (2)(3)(4)(5)(6)(7)(8) Moreover, and also critically, the TP not only mediates the actions of TXA 2 but also those of the isoprostane 8-iso-prostaglandin (PG) F 2α (also termed 15-F2t-isoprostane), a non-enzymatic-, freeradical-derived product of arachidonic acid produced in abundance during oxidative injury/hypoxia, including in various cardiovascular and pulmonary diseases. (9) Significantly in the context of PAH, 8iso-PGF 2α is increased over 3-fold in PAH patients and correlates with PAH status and disease progression.…”

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confidence: 99%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

Mulvaney¹,

Reid²,

Bialešová³

et al. 2020

Preprint

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Background NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A 2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F 2α , a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs. Methods PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar–Kyoto rats. Animals were assigned into groups: 1. ‘No MCT’; 2. ‘MCT Only’; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT. Results From haemodynamic assessments , NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals. Conclusions These findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

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Regulated expression of the TPβ isoform of the human T prostanoid receptor by the tumour suppressors FOXP1 and NKX3.1: Implications for the role of thromboxane in prostate cancer

Cited by 7 publications

References 58 publications

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

Differential expression of the TPα and TPβ isoforms of the human T Prostanoid receptor during chronic inflammation of the prostate: Role for FOXP1 in the transcriptional regulation of TPβ during monocyte-macrophage differentiation

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

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