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Cyclooxygenase and Cancer: Fundamental Molecular Investigations

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 17818

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Dr. Mauro Coluccia

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Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, Via E. Orabona 4, I-70125 Bari, Italy
Interests: anticancer drugs; targeted anticancer therapeutics; cellular response to anticancer treatment; inflammation and inflammation mediators
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Special Issue Information

Dear Colleagues,

Today, we have a very rich, perhaps overwhelming, scientific literature on cyclooxygenases and cancer. In particular, the prognostic relevance of cyclooxygenase expression, the pathophysiological mechanisms connecting cyclooxygenase products and the various features of tumor phenotype, and finally the possibility of using cyclooxygenase inhibitors in chemoprevention and therapy have been largely investigated in the last few decades.

Each of the abovementioned topics could be the subject of a collection of papers on cyclooxygenase and cancer. However, in this IJMS Special Issue, we would like to collect scientific papers mainly focusing on fundamental molecular investigations about cyclooxygenases, the relevant lipid signaling molecules, and cancer pathophysiology. Original articles and reviews concerning biochemical, molecular and cellular biology, and molecular medicine aspects are welcome. In addition to the publication of experimental research specific results as well as of high-level review articles, the founding ambition of this IJMS special issue is to render a concretely useful service to the oncological research community interested in cyclooxygenase and cancer relationship. To this end, all authors of experimental papers are warmly invited to provide a state-of-the-art and careful description of the topic under investigation as far as the scientific content and technology/methodology issues are concerned. Moreover, it is recommended that the discussion/conclusion section, generally devoted to the “strong points”, future directions and/or clinical impact of the findings, includes also the potential limitations of the study.

From all contributions as a whole, we hope that people already working on specific topics are successfully updated on issues not directly linked to their research activity, and that possible concerns of people approaching this fascinating and complex cyclooxygenase and cancer relationship might be at least partly reduced.

Prof. Mauro Coluccia
Guest Editor

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Keywords

cyclooxygenase
cyclooxygenase inhibitor
prostaglandin
eicosanoid
lipid signaling molecules
cancer biology
cancer pathophysiology

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Published Papers (6 papers)

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Editorial

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5 pages, 206 KiB

Open AccessEditorial

Cyclooxygenase and Cancer: Fundamental Molecular Investigations

by Mauro Coluccia

Int. J. Mol. Sci. 2023, 24(15), 12342; https://doi.org/10.3390/ijms241512342 - 2 Aug 2023

Cited by 4 | Viewed by 1056

Abstract

The involvement of prostaglandins in cancer was first observed in human esophageal carcinoma cells, whose invasive and metastatic potential in nude mice was found to be related to PGE₂ and PGF_2a production [...] Full article

(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)

Research

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23 pages, 18668 KiB

Open AccessArticle

Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro

by Matthew Thomas Ferreira, Juliano Andreoli Miyake, Renata Nascimento Gomes, Fábio Feitoza, Pollyana Bulgarelli Stevannato, Andrew Silva da Cunha, Fernanda de Oliveira Serachi, Alexandros Theodoros Panagopoulos and Alison Colquhoun

Int. J. Mol. Sci. 2021, 22(9), 4297; https://doi.org/10.3390/ijms22094297 - 21 Apr 2021

Cited by 12 | Viewed by 2331

Abstract

Prostaglandin E₂ (PGE₂) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE₂ receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE₂ and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE₂ in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE₂. In T98G cells exogenous PGE₂ increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE₂ signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development. Full article

(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)

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15 pages, 11869 KiB

Open AccessArticle

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

by Cheng-Yi Chang, Ping-Ho Pan, Jian-Ri Li, Yen-Chuan Ou, Jiaan-Der Wang, Su-Lan Liao, Wen-Ying Chen, Wen-Yi Wang and Chun-Jung Chen

Int. J. Mol. Sci. 2020, 21(12), 4219; https://doi.org/10.3390/ijms21124219 - 13 Jun 2020

Cited by 17 | Viewed by 3191

Abstract

Clinically, high cyclooxygenase-2 expression in malignant glioma correlates well with poor prognosis and the use of aspirin is associated with a reduced risk of glioma. To extend the current understanding of the apoptotic potential of aspirin in most cell types, this study provides evidence showing that aspirin induced glioma cell apoptosis and inhibited tumor growth, in vitro and in vivo. We found that the human H4 glioma cell-killing effects of aspirin involved mitochondria-mediated apoptosis accompanied by endoplasmic reticulum (ER) stress, Noxa upregulation, Mcl-1 downregulation, Bax mitochondrial distribution and oligomerization, and caspase 3/caspase 8/caspase 9 activation. Genetic silencing of Noxa or Bax attenuated aspirin-induced viability loss and apoptosis, while silencing Mcl-1 augmented the effects of aspirin. Data from genetic and pharmacological studies revealed that the axis of ER stress comprised an apoptotic cascade leading to Noxa upregulation and apoptosis. The apoptotic programs and mediators triggered by aspirin in H4 cells were duplicated in human U87 glioma cell line as well as in tumor-bearing BALB/c nude mice. The involvement of ER stress in indomethacin-induced Mcl-1 downregulation was reported in our previous study on glioma cells. Therefore, the aforementioned phenomena indicate that ER stress may be a valuable target for intervention in glioma apoptosis. Full article

(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)

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17 pages, 2689 KiB

Open AccessArticle

Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation

by Esraa Saadi, Rapita Sood, Ido Dromi, Ranin Srouji, Ossama Abu Hatoum, Sharon Tal and Liza Barki-Harrington

Int. J. Mol. Sci. 2020, 21(9), 3195; https://doi.org/10.3390/ijms21093195 - 30 Apr 2020

Cited by 3 | Viewed by 3129

Abstract

Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presented herein show that a K598R point mutation at the carboxyl-terminus of COX-2 causes the appearance of several COX-2 immunoreactive fragments in nuclear compartments, and significantly enhances cell proliferation. In contrast, insertion of additional mutations at the border of the membrane-binding and catalytic domains of K598R COX-2 blocks fragment formation and prevents the increase in proliferation. Transcriptomic analyses show that K598R COX-2 significantly affects the expression of genes involved in RNA metabolism, and subsequent proteomics suggest that it is associated with proteins that regulate mRNA processing. We observe a similar increase in proliferation by expressing just that catalytic domain of COX-2 (ΔNT- COX-2), which is completely devoid of catalytic activity in the absence of its other domains. Moreover, we show that the ΔNT- COX-2 protein also interacts in the nucleus with β-catenin, a central regulator of gene transcription. Together these data suggest that the cleavage products of COX-2 can affect cell proliferation by mechanisms that are independent of prostaglandin synthesis. Full article

(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)

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13 pages, 2742 KiB

Open AccessArticle

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis

by Cheng-Yi Chang, Jian-Ri Li, Chih-Cheng Wu, Jiaan-Der Wang, Su-Lan Liao, Wen-Ying Chen, Wen-Yi Wang and Chun-Jung Chen

Int. J. Mol. Sci. 2020, 21(2), 557; https://doi.org/10.3390/ijms21020557 - 15 Jan 2020

Cited by 22 | Viewed by 3701

Abstract

The dormancy of cellular apoptotic machinery has been highlighted as a crucial factor in therapeutic resistance, recurrence, and poor prognosis in patients with malignancy, such as malignant glioma. Increasing evidence indicates that nonsteroidal anti-inflammatory drugs (NSAIDs) confer chemopreventive effects, and indomethacin has been shown to have a novel chemotherapeutic application targeting glioma cells. To extend these findings, herein, we studied the underlying mechanisms of apoptosis activation caused by indomethacin in human H4 and U87 glioma cells. We found that the glioma cell-killing effects of indomethacin involved both death receptor- and mitochondria-mediated apoptotic cascades. Indomethacin-induced glioma cell apoptosis was accompanied by a series of biochemical changes, including reactive oxygen species generation, endoplasmic reticulum (ER) stress, apoptosis signal-regulating kinase-1 (Ask1) activation, p38 hyperphosphorylation, protein phosphatase 2A (PP2A) activation, Akt dephosphorylation, Mcl-1 and FLICE-inhibiting protein (FLIP) downregulation, Bax mitochondrial distribution, and caspases 3/caspase 8/caspase 9 activation. Data on pharmacological inhibition related to oxidative stress, ER stress, free Ca²⁺, and p38 revealed that the axis of oxidative stress/ER stress/Ask1/p38/PP2A/Akt comprised an apoptotic cascade leading to Mcl-1/FLIP downregulation and glioma apoptosis. Since indomethacin is an emerging choice in chemotherapy and its antineoplastic effects have been demonstrated in glioma tumor-bearing models, the findings further strengthen the argument for turning on the aforementioned axis in order to activate the apoptotic machinery of glioma cells. Full article

(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)

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16 pages, 3308 KiB

Open AccessArticle

Multifocal Signal Modulation Therapy by Celecoxib: A Strategy for Managing Castration-Resistant Prostate Cancer

by Roberto Benelli, Paola Barboro, Delfina Costa, Simonetta Astigiano, Ottavia Barbieri, Matteo Capaia, Alessandro Poggi and Nicoletta Ferrari

Int. J. Mol. Sci. 2019, 20(23), 6091; https://doi.org/10.3390/ijms20236091 - 3 Dec 2019

Cited by 11 | Viewed by 3768

Abstract

Background: Prostate cancer (PCa) is a significant health concern throughout the world. Standard therapy for advanced disease consists of anti-androgens, however, almost all prostate tumors become castration resistant (CRPC). Progression from androgen-sensitive PCa to CRPC is promoted by inflammatory signaling through cyclooxygenase-2 (COX-2) expression and ErbB family receptors/AKT activation, compensating androgen receptor inactivity. Methods: Making use of CRPC cell lines, we investigated the effects of the anti-inflammatory drug celecoxib. Biochemical data obtained using immunoblotting, enzyme-linked immunosorbent assay (ELISA), invasion, and xenografts were further integrated by bioinformatic analyses. Results: Celecoxib reduced cell growth and induced apoptosis through AKT blockade, cleavage of poly (ADP-ribose) polymerase-1 (PARP-1), and proteasomal degradation of the anti-apoptotic protein Mcl-1. Epidermal growth factor receptor (EGFR), ErbB2, and ErbB3 degradation, and heterogeneous nuclear ribonucleoprotein K (hnRNP K) downregulation, further amplified the inhibition of androgen signaling. Celecoxib reduced the invasive phenotype of CRPC cells by modulating NF-κB activity and reduced tumor growth in mice xenografts when administered in association with the anti-EGFR receptor antibody cetuximab. Bioinformatic analyses on human prostate cancer datasets support the relevance of these pathways in PCa progression. Conclusions: Signaling nodes at the intersection of pathways implicated in PCa progression are simultaneously modulated by celecoxib treatment. In combination therapies with cetuximab, celecoxib could represent a novel therapeutic strategy to curb signal transduction during CRPC progression. Full article

(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)

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