Application of small molecule FPR1 antagonists in the treatment of cancers

Ahmet, Djevdet S.; Basheer, Haneen A.; Salem, A. R.; Lu, Di; Aghamohammadi, Amin; Weyerhäuser, Patrick; Bordiga, Andrea; Almeniawi, Juman; Rashid, Sabah; Cooper, Patricia A.; Shnyder, Steven D.; Vinader, V.; Afarinkia, K.

doi:10.1038/s41598-020-74350-z

Cited by 10 publications

(7 citation statements)

References 48 publications

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“…These genes were mainly enriched in small molecule metabolic processes, cellular protein metabolic processes and cellular lipid metabolic processes. Studies of human primary and metastatic tumour tissue samples have shown that the metabolism of many small molecules is associated with the metastasis of tumours 41 – 43 . For example, the expression of the small-molecule inhibitor CKB is enhanced in liver metastases and inhibits extracellular small molecule metabolism.…”

Section: Discussionmentioning

confidence: 99%

PCBP1 regulates the transcription and alternative splicing of metastasis‑related genes and pathways in hepatocellular carcinoma

Huang

Luo

Jiang

et al. 2021

Sci Rep

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PCBP1 is a multifunctional RNA-binding protein (RBP) expressed in most human cells and is involved in posttranscriptional gene regulation. PCBP1 regulates the alternative splicing, translation and RNA stability of many cancer-related genes and has been identified as a potential tumour suppressor gene. PCBP1 inhibits the invasion of hepatocellular carcinoma (HCC) cells, but there are few studies on the specific regulatory target and mechanism of RBPs in HCC, and it is unclear whether PCBP1 plays a role in tumour metastasis as a splicing factor. We analysed the regulation of gene expression by PCBP1 at the transcriptional level. We obtained and analysed PCBP1-knockdown RNA-seq data and eCLIP-seq data of PCBP1 in HepG2 cells and found that PCBP1 widely regulates the alternative splicing and expression of genes enriched in cancer-related pathways, including extracellular matrix, cell adhesion, small molecule metabolic process and apoptosis. We validated five regulated alternative splicing events affected by PCBP1 using RT-qPCR and found that there was a significant difference in the expression of APOC1 and SPHK1 between tumour and normal tissues. In this study, we provided convincing evidence that human PCBP1 profoundly regulates the splicing of genes associated with tumour metastasis. These findings provide new insight into potential markers or therapeutic targets for HCC treatment.

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Section: Discussionmentioning

confidence: 99%

PCBP1 regulates the transcription and alternative splicing of metastasis‑related genes and pathways in hepatocellular carcinoma

Huang

Luo

Jiang

et al. 2021

Sci Rep

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“…Although the expression of FPR1 in healthy, non-immune cells is low, a number of tumors have been shown to express significant levels of FPR1 (25)(26)(27)(28)(29)(30). Importantly, a previous study indicated that targeting FPR1 by ICT12035, a selective small molecule antagonist, can provide a new avenue for the therapy of cancers (31). Therefore, further investigation of FPR1 antagonists can provide opportunities for more efficient treatment of cancers, including bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

An Exploration of the Tumor Microenvironment Identified a Novel Five-Gene Model for Predicting Outcomes in Bladder Cancer

Feng

Sun

et al. 2021

Front. Oncol.

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Bladder cancer (BC) is one of the top ten most common cancer types globally, accounting for approximately 7% of all male malignancies. In the last few decades, cancer research has focused on identifying oncogenes and tumor suppressors. Recent studies have revealed that the interplay between tumor cells and the tumor microenvironment (TME) plays an important role in the initiation and development of cancer. However, the current knowledge regarding its effect on BC is scarce. This study aims to explore how the TME influences the development of BC. We focused on immune and stromal components, which represent the major components of TME. We found that the proportion of immune and stromal components within the TME was associated with the prognosis of BC. Furthermore, based on the scores of immune and stromal components, 811 TME-related differentially expressed genes were identified. Three subclasses with distinct biological features were divided based on these TME-genes. Finally, five prognostic genes were identified and used to develop a prognostic prediction model for BC patients based on TME-related genes. Additionally, we validated the prognostic value of the five-gene model using three independent cohorts. By further analyzing features based on the five-gene signature, higher CD8+ T cells, higher tumor mutational burden, and higher chemosensitivity were found in the low-risk group, which presented a better prognosis. In conclusion, our exploration comprehensively analyzed the TME and identified TME-related prognostic genes for BC, providing new insights into potential therapeutic targets.

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“…To date, a variety of synthetic molecules have been identified that antagonize and/or inhibit FPR1‐mediated responses. Among the large number of different FPR1 inhibitors, the most potent and selective compounds described so far, belong to a group of novel pyrazoles 85–87 . These FPR1 antagonists are not commercially available but they might be important tool compounds for future studies of the role of this receptor in initiation as well as the resolution of inflammatory reactions.…”

Section: Defined Neutrophil Gpcrsmentioning

confidence: 99%

G protein coupled pattern recognition receptors expressed in neutrophils: Recognition, activation/modulation, signaling and receptor regulated functions

Dahlgren

Lind

Mårtensson

et al. 2022

Immunological Reviews

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Summary Neutrophils, the most abundant white blood cell in human blood, express receptors that recognize damage/microbial associated pattern molecules of importance for cell recruitment to sites of inflammation. Many of these receptors belong to the family of G protein coupled receptors (GPCRs). These receptor‐proteins span the plasma membrane in expressing cells seven times and the down‐stream signaling rely in most cases on an activation of heterotrimeric G proteins. The GPCRs expressed in neutrophils recognize a number of structurally diverse ligands (activating agonists, allosteric modulators, and inhibiting antagonists) and share significant sequence homologies. Studies of receptor structure and function have during the last 40 years generated important information on GPCR biology in general; this knowledge aids in the overall understanding of general pharmacological principles, governing regulation of neutrophil function and inflammatory processes, including novel leukocyte receptor activities related to ligand recognition, biased/functional selective signaling, allosteric modulation, desensitization, and reactivation mechanisms as well as communication (receptor transactivation/cross‐talk) between GPCRs. This review summarizes the recent discoveries and pharmacological hallmarks with focus on some of the neutrophil expressed pattern recognition GPCRs. In addition, unmet challenges, including recognition by the receptors of diverse ligands and how biased signaling mediate different biological effects are described/discussed.

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Application of small molecule FPR1 antagonists in the treatment of cancers

Cited by 10 publications

References 48 publications

PCBP1 regulates the transcription and alternative splicing of metastasis‑related genes and pathways in hepatocellular carcinoma

PCBP1 regulates the transcription and alternative splicing of metastasis‑related genes and pathways in hepatocellular carcinoma

An Exploration of the Tumor Microenvironment Identified a Novel Five-Gene Model for Predicting Outcomes in Bladder Cancer

G protein coupled pattern recognition receptors expressed in neutrophils: Recognition, activation/modulation, signaling and receptor regulated functions

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