The roles of the COX2/PGE2/EP axis in therapeutic resistance

Tong, Dali; Liu, Qiuli; Wang, Lin-Ang; Xie, Qiubo; Pang, Junfeng; Huang, Yi; Wang, Luofu; Liu, Gaolei; Zhang, Dianzheng; Lan, Weihua; Jiang, Jun

doi:10.1007/s10555-018-9752-y

Cited by 71 publications

(67 citation statements)

References 129 publications

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“…Therapeutic Efficacy. Because COX-2 is associated with tumor promotion and therapeutic resistance (54,55), we hypothesized that targeting COX-2 activity would inhibit the ability of ruxolitinib-treated macrophages to promote resistance of TNBC cells to ruxolitinib. Celecoxib effectively reduced the PGE2 production by ruxolitinib-treated human primary macrophages (Fig.…”

Section: Celecoxib In Combination With Ruxolitinib Leads To Enhancedmentioning

confidence: 99%

JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

Irey

Lassiter

Brady

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the protumorigenic factor cyclooxygenase-2 (COX-2), and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.

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Section: Celecoxib In Combination With Ruxolitinib Leads To Enhancedmentioning

confidence: 99%

JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

Irey

Lassiter

Brady

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…In parallel, the COX2/PGE2/EP axis appears as a pivotal key not only in tumor initiation and progression but also in the development of therapeutic resistance. 58 Overexpression of COX2 and mPGES-1 (microsomal prostaglandin E synthase) are commonly detected in penile intraepithelial neoplasia and carcinoma. 24 Herein, we demonstrated the genetic mechanism related to the overexpression of COX2 by demonstrating its higher production at mRNA and protein levels.…”

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confidence: 99%

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

Macedo

Silva

Nogueira³

et al. 2020

Molecular Carcinogenesis

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The incidence of penile cancer (PeCa) is increasing worldwide, however, the highest rates are reported in underdeveloped countries. The molecular mechanisms that underly the onset and progression of these tumors are still unclear. Therefore, our goal was to determine the genome-wide copy number alterations and the involvement of human papiloma virus (HPV) (TP53 and RB1), inflammatory (COX2 and EGFR), and PI3K/AKT pathway (AKT1, AKT2, EGFR, ERBB3, ERBB4, PIK3CA, and PTEN) associated genes in patients with PeCa from a high incidence region in Brazil (Maranhão). HPV genotyping was performed by nest-PCR and genome sequencing, copy number alterations (CNAs) by array comparative genomic hybridization and gene copy number status, gene, and protein expression by quantitative polymerase chain reaction, reverse transcriptasequantitative polymerase chain reaction, and immunohistochemistry, respectively.HPV genotyping revealed one of the highest frequencies of HPV reported in PeCa, affecting 96.4% of the cases. The most common CNAs observed were located at the HPV integration sites, such as 2p12-p11.2 and 14q32.33, where Abbreviations: aCGH, array comparative genomic hybridization; CNA, copy number alteration; Cq, quantification cycle; FFPE, formalin-fixed paraffin-embedded; HPV, human papiloma virus;HrHPV, High risk HPV; IHCi, mmunohistochemistry; PCR, polymerase chain reaction; PeCa, penile cancer; qPCR, quantitative polymerase chain reaction; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction; TMA, tissue microarray. ADAM 6, KIAA0125, LINC00226, LINC00221, and miR7641-2, are mapped. Increased copy number of ERBB3 and EGFR genes were observed in association with COX2 and EGFR overexpression, reinforcing the role of the inflammatory pathway in PeCa, and suggesting anti-EGFR and anti-COX2 inhibitors as promising therapies for PeCa. Additionally, TP53 and RB1 messenger RNA downregulation was observed, suggesting the occurrence of other mechanisms for repression of these oncoproteins, in addition to the canonical HPV/TP53/RB1 signaling pathway. Our data reinforce the role of epigenetic events in abnormal gene expression in HPV-associated carcinomas and suggest the pivotal role of HPV driving CNAs and controlling gene expression in PeCa. K E Y W O R D Scarcinoma of the penis, genomic alterations, human papillomavirus, molecular markers

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“…Constitutive COX2 expression is triggered by pathways activated by oncogenic stimuli and cyto-chemokines, such as MAPK, PI3K/AKT and NFkB that are frequently hyperexpressed in most of resistant tumors [ 17 ]. Upregulation of the COX2/PGE2 axis favors proliferation, angiogenesis, invasion, apoptosis resistance, and the activation of immunosuppressive cells contributing to tumor progression and therapy resistance [ 43 ]. We showed that COX2 and PTGES are both overexpressed in several BRAF/MEKi-resistant melanoma cells and tumor tissues, and that COX2 knockdown significantly enhanced drug effects in melanoma cell.…”

Section: Discussionmentioning

confidence: 99%

miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

et al. 2020

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Background Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance. Methods The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy. Results miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor. Conclusions Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Graphical Abstract

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The roles of the COX2/PGE2/EP axis in therapeutic resistance

Cited by 71 publications

References 129 publications

JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

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