The Serine Protease CD26/DPP4 in Non-Transformed and Malignant T Cells

Chitadze, Guranda; Wehkamp, Ulrike; Janßen, Ottmar; Brüggemann, Monika; Lettau, Marcus

doi:10.3390/cancers13235947

Cited by 13 publications

(16 citation statements)

References 143 publications

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“…For instance, APN is of diagnostic and/or prognostic relevance for patients with pancreatic, colon, and non-small cell lung cancer [5,6,9]. DPP4 is reported as a positive prognostic factor in ovarian cancer [287] and an established marker for diagnosis in cutaneous T cell lymphoma [288]. For the short term, it can be expected that FAP specific imaging will contribute to a better patient stratification and follow-up of therapy in several solid tumours [14,289].…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Verhulst

Garnier

Meester

et al. 2022

Cancers

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Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.

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Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Verhulst

Garnier

Meester

et al. 2022

Cancers

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“…Analysis of the crystal structure of DPP4 distinguishes two domains in the extracellular part: a β-propeller and a catalytic α/β hydrolase domain [ 16 , 20 ]. The β-propeller is open, has eight blades [ 21 ] and encompasses two subdomains: the glycosylation-rich region (blades II–V) and the cysteine-rich region (blades VI–VIII) [ 8 , 15 , 16 , 22 ]. The regions constituting the β-propeller could serve to interact with other proteins and be involved in non-enzymatic functions of DPP4 [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

“…The regions constituting the β-propeller could serve to interact with other proteins and be involved in non-enzymatic functions of DPP4 [ 23 ]. For example, ADA binds to the glycosylation-rich region of DPP4, and matrix proteins such as collagen to the cysteine-rich region [ 17 , 19 , 20 , 22 , 24 ]. On the other hand, the α/β hydrolase domain harbors the catalytic triad (Ser630/Asp708/His740) required for DPP4 activity [ 20 , 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology

et al. 2022

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DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as it has been already demonstrated for other coronaviruses. In this review, we analyze the evidence for the role of DPP4 on COVID-19 risk and clinical outcome, and its contribution to COVID-19 physiopathology. Due to the pathogenetic links between COVID-19 and diabetes mellitus and the hyperinflammatory response, with the hallmark cytokine storm developed very often during the disease, we dive deep into the functions of DPP4 on carbohydrate metabolism and immune system regulation. We show that the broad spectrum of functions regulated by DPP4 is performed both as a protease enzyme, as well as an interacting partner of other molecules on the cell surface. In addition, we provide an update of the DPP4 inhibitors approved by the EMA and/or the FDA, together with the newfangled approval of generic drugs (in 2021 and 2022). This review will also cover the effects of DPP4 inhibitors (i.e., gliptins) on the progression of SARS-CoV-2 infection, showing the role of DPP4 in this disturbing disease.

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“…F11R is required for the proliferation and migration of inflamed smooth muscle cells, thereby playing an important role in the subsequent growth of atherosclerotic plaques ( Azari et al, 2010 ). DPP4 is a transmembrane serine protease that cleaves off N-terminal dipeptides ( Chitadze et al, 2021 ; Love and Liu, 2021 ), which are highly involved in glucose and insulin metabolism as well as in immune regulation. VAV3 encodes the protein of a Rho family GTPase that regulates cell signalling pathways, including those of T- and B-cell receptors, by mediating the activities of Rho family members ( Shen et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Immune-Related Gene Signature in Stanford Type A Aortic Dissection

Wang

et al. 2022

Front. Genet.

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Background: Stanford type A aortic dissection (ATAAD) is a common life-threatening event in the aorta. Recently, immune disorder has been linked to the risk factors that cause ATAAD at the molecular level. However, the specific immune-related gene signature during the progression is unclear.Methods: The GSE52093 and GSE98770 datasets related to ATAAD from the Gene Expression Omnibus (GEO) database were acquired. The immune gene expression levels were analyzed by single sample gene set enrichment analysis (ssGSEA). The correlations between gene networks and immune scores were determined by weighted gene correlation network analysis (WGCNA). The different immune subgroups were finally divided by consensus clustering. The differentially expressed genes (DEGs) were identified and subsequent functional enrichment analyses were conducted. The hub genes were identified by protein–protein interaction (PPI) network and functional similarities analyses. The immune cell infiltration proportion was determined by the CIBERSORT algorithm.Results: According to the ssGSEA results, the 13 ATAAD samples from the GEO database were divided into high- and low-immune subgroups according to the ssGSEA, WGCNA, and consensus clustering analysis results. Sixty-eight immune-related DEGs (IRDEGs) between the two subgroups were enriched in inflammatory-immune response biological processes, including leukocyte cell–cell adhesion, mononuclear cell migration, and myeloid leukocyte migration. Among these IRDEGs, 8 genes (CXCR4, LYN, CCL19, CCL3L3, SELL, F11R, DPP4, and VAV3) were identified as hub genes that represented immune-related signatures in ATAAD after the PPI and functional similarities analyses. The proportions of infiltrating CD8 T cells and M1 macrophages were significantly higher in ATAAD patients in the immune-high group than the immune-low group.Conclusion: Eight immune-related genes were identified as hub genes representing potential biomarkers and therapeutic targets linked to the immune response in ATAAD patients.

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The Serine Protease CD26/DPP4 in Non-Transformed and Malignant T Cells

Cited by 13 publications

References 143 publications

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology

Identification of Immune-Related Gene Signature in Stanford Type A Aortic Dissection

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