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Khezri MR, Pashaei MR, Ghasemnejad-Berenji M, Ghasemnejad-Berenji H. Sitagliptin exhibits protective effects against methotrexate-induced testicular toxicity: The involvement of oxidative stress-related factors. Reprod Toxicol 2024; 129:108672. [PMID: 39043351 DOI: 10.1016/j.reprotox.2024.108672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/20/2024] [Accepted: 07/20/2024] [Indexed: 07/25/2024]
Abstract
Methotrexate (MTX) is widely prescribed to treat different malignancies as well as autoimmune diseases. However, it causes a range of side effects in different organs such as testis. This study aims to clarify the role of dipeptidyl peptidase 4 (DPP4) in MTX-induced testicular damage via pathways involved in oxidative stress and evaluates the protective effects of sitagliptin as a DPP4 inhibitor. Twenty-four animals randomly allocated into four groups including: (I) control, (II) MTX (20 mg/kg, i.p.), (III) sitagliptin (20 mg/kg, i.p., for four consecutive days), and MTX + sitagliptin in which received chemicals resembling group II and III. Histopathological examinations conducted to assess the structural changes in testes of different experimental groups. Also, ELISA method employed to investigate the levels of DPP4, AKT, p-AKT, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). In addition, the total malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) were assessed. The results indicated that MTX administration was accompanied with testicular damage, which reversed by sitagliptin treatment. The biochemical observations demonstrated that MTX markedly increased the levels of DPP4, decreased p-AKT/AKT ratio followed by a marked decrement in Nrf2 and HO-1 levels. Also, it was observed that MTX decreased the activity of SOD and increased total MDA content in testicular specimen. However, sitagliptin treatment diminished mentioned alterations effectively. Altogether, our findings supported the possible role of DPP4 in MTX-induced testicular toxicity along with the potential protective features of sitagliptin via suppressing of the histopathological and biochemical alterations induced by MTX.
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Affiliation(s)
- Mohammad Rafi Khezri
- Reproductive Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Reza Pashaei
- Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Morteza Ghasemnejad-Berenji
- Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran; Research Center for Experimental and Applied Pharmaceutical Sciences, Urmia University of Medical Sciences, Urmia, Iran
| | - Hojat Ghasemnejad-Berenji
- Reproductive Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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2
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Guilhem A, Portalès P, Dupuis-Girod S, Rivière S, Vincent T. Altered expressions of CXCR4 and CD26 on T-helper lymphocytes in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2021; 16:511. [PMID: 34906163 PMCID: PMC8670161 DOI: 10.1186/s13023-021-02139-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 11/28/2021] [Indexed: 11/10/2022] Open
Abstract
Background Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by a deregulated neo-angiogenesis. Besides a mainly vascular phenotype (muco-cutaneous telangiectases, arteriovenous malformations), a specific risk of infection is suggested by case series of severe and atypical infections as well as by reports of decreased T and natural killer (NK) lymphocyte counts. As some evidence supports a dysregulation of the CXCR4/CXCL12 chemotactic axis of HHT endothelial cells, we hypothesized that a similar phenomenon could occur on lymphocytes. Methods Eighteen HHT patients with history of severe infection (HSI) were matched in age and sex with 18 HHT without HSI and 18 healthy control subjects (HC). We assessed the cell count and the surface expression of CXCR4 and CD26 (CXCL12 inactivating peptidase) of circulating T-helper and T-cytotoxic lymphocytes (including naive, memory and activated subsets) and NK cells. Results The overall HHT group of 36 patients exhibited a reduction of circulating T-helper lymphocytes compared to HC (median: 517 vs. 1026 cells/mm3, p < 0.0001), correlated with age (r = − 0.46, p = 0.005), requirement of intravenous iron or blood transfusions (median: 291 vs. 627 cells/mm3, p = 0.03) and CXCR4 surface expression (r = 0.353, p = 0.0345). CXCR4 and CD26 membrane expression were both decreased on HHT T-helper lymphocytes (median MFI ratio: 4.49 vs. 5.74 for CXCR4 and 3.21 vs. 4.33 for CD26, p = 0.03 and 0.0018 respectively) with an unchanged CXCR4/CD26 ratio. The HHT group with HSI had a higher CXCR4/CD26 ratio on the total T-lymphocyte population, as well as on the T-helper population and its naive subset (median on naive T-helper cells: 2.34 vs. 1.32, p = 0.0002). Conclusions Our findings support a dysregulation of the CXCL12/CXCR4 chemotaxis of T-helper lymphocytes in HHT patients, potentially linked to their T-helper lymphopenia and susceptibility to infection. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-02139-y.
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Affiliation(s)
- Alexandre Guilhem
- CHU de Montpellier, Médecine interne et maladies multi-organiques de l'adulte, Hôpital Saint Eloi, Montpellier, France.
| | - Pierre Portalès
- CHU de Montpellier, Laboratoire d'immunologie, Hôpital Saint Eloi, Montpellier, France
| | - Sophie Dupuis-Girod
- Centre National de référence Maladie de Rendu-Osler, Service de génétique Hôpital Mère-Enfant, Hospices Civils de Lyon, Bron, France
| | - Sophie Rivière
- CHU de Montpellier, Médecine interne et maladies multi-organiques de l'adulte, Hôpital Saint Eloi, Montpellier, France
| | - Thierry Vincent
- CHU de Montpellier, Laboratoire d'immunologie, Hôpital Saint Eloi, Montpellier, France
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CD26-Related Serum Biomarkers: sCD26 Protein, DPP4 Activity, and Anti-CD26 Isotype Levels in a Colorectal Cancer-Screening Context. DISEASE MARKERS 2020; 2020:4347936. [PMID: 32051696 PMCID: PMC6995486 DOI: 10.1155/2020/4347936] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 11/07/2019] [Accepted: 12/04/2019] [Indexed: 12/14/2022]
Abstract
Current screening trials are showing reduction in colorectal cancer incidence and mortality. However, participation rates are often low, and blood-based tests could complement existing screening strategies. CD26 protein (sCD26) and its dipeptidyl peptidase IV (DPP4) enzymatic activity in circulation have been proposed as biomarkers for colorectal cancer and other diseases. However, changes in sCD26 and DPP4 levels show complex degrees of correlation, and their physiological or pathophysiological role is unclear. The aim of this study was to analyse if anti-CD26 autoantibodies are related to sCD26 and DPP4 and to determine their relevance in a context of colorectal cancer screening for complementing the value of sCD26 and DPP4 as biomarkers. These biomarkers were measured in a large prospective cohort (n = 497, except the anti-CD26 antibodies, evaluated in 125 samples) that included a subgroup of individuals that were positive for the faecal immunological occult blood test (FIT) (n = 86) and underwent a colonoscopy (n = 47). We confirmed for the first time higher DPP4 activity in men compared to women (Student's t test, p = 0.002), though this difference between sexes was not seen for serum sCD26 protein. These biomarkers correlated (R = 0.246, p = 0.003) only in women. Correlations were found between anti-CD26 isotypes but not with DPP4 activity or sCD26 concentration, except for a negative correlation only in men between anti-CD26 IgA isotype and sCD26 (R = -0.232, p = 0.044), and an almost significant negative correlation between anti-CD26 IgG and sCD26 limited to FIT-positive men. Interestingly, patients with advanced adenomas displayed the most elevated mean levels of anti-CD26 IgA, IgM, and particularly IgG (Mann-Whitney U test, p = 0.030) in comparison with the other FIT positives without adenomas, and these levels did not correlate with sCD26 or its DPP4 activity. Our preliminary results suggest that the combination of these measures using sex as confounder could perhaps be used as biomarkers for colorectal disease. It also suggests that events affecting the gut influence the levels of anti-CD26 antibodies, which show little or no effect in antigen clearance. These findings should be confirmed in a larger cohort of individuals with colonoscopy. The physiological origin of the sex differences observed should be further addressed.
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Nieto-Fontarigo JJ, González-Barcala FJ, San José E, Arias P, Nogueira M, Salgado FJ. CD26 and Asthma: a Comprehensive Review. Clin Rev Allergy Immunol 2019; 56:139-160. [PMID: 27561663 PMCID: PMC7090975 DOI: 10.1007/s12016-016-8578-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Asthma is a heterogeneous and chronic inflammatory family of disorders of the airways with increasing prevalence that results in recurrent and reversible bronchial obstruction and expiratory airflow limitation. These diseases arise from the interaction between environmental and genetic factors, which collaborate to cause increased susceptibility and severity. Many asthma susceptibility genes are linked to the immune system or encode enzymes like metalloproteases (e.g., ADAM-33) or serine proteases. The S9 family of serine proteases (prolyl oligopeptidases) is capable to process peptide bonds adjacent to proline, a kind of cleavage-resistant peptide bonds present in many growth factors, chemokines or cytokines that are important for asthma. Curiously, two serine proteases within the S9 family encoded by genes located on chromosome 2 appear to have a role in asthma: CD26/dipeptidyl peptidase 4 (DPP4) and DPP10. The aim of this review is to summarize the current knowledge about CD26 and to provide a structured overview of the numerous functions and implications that this versatile enzyme could have in this disease, especially after the detection of some secondary effects (e.g., viral nasopharyngitis) in type II diabetes mellitus patients (a subset with a certain risk of developing obesity-related asthma) upon CD26 inhibitory therapy.
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Affiliation(s)
- Juan J Nieto-Fontarigo
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Francisco J González-Barcala
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
- Respiratory Department, Clinic University Hospital (CHUS), Santiago de Compostela, Spain
| | - Esther San José
- Clinical Analysis Service, Clinic University Hospital (CHUS), Santiago de Compostela, Spain
| | - Pilar Arias
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Montserrat Nogueira
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Francisco J Salgado
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain.
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5
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Enz N, Vliegen G, De Meester I, Jungraithmayr W. CD26/DPP4 - a potential biomarker and target for cancer therapy. Pharmacol Ther 2019; 198:135-159. [PMID: 30822465 DOI: 10.1016/j.pharmthera.2019.02.015] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CD26/dipeptidyl peptidase (DPP)4 is a membrane-bound protein found in many cell types of the body, and a soluble form is present in body fluids. There is longstanding evidence that various primary tumors and also metastases express CD26/DPP4 to a variable extent. By cleaving dipeptides from peptides with a proline or alanine in the penultimate position at the N-terminus, it regulates the activity of incretin hormones, chemokines and many other peptides. Due to these effects and interactions with other molecules, a tumor promoting or suppressing role can be attributed to CD26/DPP4. In this review, we discuss the existing evidence on the expression of soluble or membrane-bound CD26/DPP4 in malignant diseases, along with the most recent findings on CD26/DPP4 as a therapeutic target in specific malignancies. The expression and possible involvement of the related DPP8 and DPP9 in cancer are also reviewed. A higher expression of CD26/DPP4 is found in a wide variety of tumor entities, however more research on CD26/DPP4 in the tumor microenvironment is needed to fully explore its use as a tumor biomarker. Circulating soluble CD26/DPP4 has also been studied as a cancer biomarker, however, the observed decrease in most cancer patients does not seem to be cancer specific. Encouraging results from experimental work and a recently reported first phase clinical trial targeting CD26/DPP4 in mesothelioma, renal and urological tumors pave the way for follow-up clinical studies, also in other tumor entities, possibly leading to the development of more effective complementary therapies against cancer.
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Affiliation(s)
- Njanja Enz
- Department of Thoracic Surgery, University Hospital Rostock, Schillingallee 35, 18057 Rostock, Germany
| | - Gwendolyn Vliegen
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Ingrid De Meester
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
| | - Wolfgang Jungraithmayr
- Department of Thoracic Surgery, University Hospital Rostock, Schillingallee 35, 18057 Rostock, Germany.
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Chang JH, Cheng CW, Yang YC, Chen WS, Hung WY, Chow JM, Chen PS, Hsiao M, Lee WJ, Chien MH. Downregulating CD26/DPPIV by apigenin modulates the interplay between Akt and Snail/Slug signaling to restrain metastasis of lung cancer with multiple EGFR statuses. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:199. [PMID: 30134935 PMCID: PMC6104010 DOI: 10.1186/s13046-018-0869-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 08/08/2018] [Indexed: 11/10/2022]
Abstract
BACKGROUND Metastasis rather than the primary cancer determines the survival of cancer patients. Activation of Akt plays a critical role in the epithelial-to-mesenchymal transition (EMT), the initial step in lung cancer metastasis. Apigenin (API), a flavonoid with a potent Akt-inhibitory effect, shows oncostatic activities in various cancers. However, the effects of API on metastasis of non-small cell lung cancer (NSCLC) remain unclear. METHODS NSCLC cell lines with different epidermal growth factor receptor (EGFR) statuses and in vivo orthotopic bioluminescent xenograft model were employed to determine antitumor activity of API. Western blot and genetic knockdown by shRNA or genetic overexpression by DNA plasmids were performed to explore the underlying mechanisms. The Cancer Genome Atlas (TCGA) database was used to investigate the prognosis of API-targeted genes. RESULTS API was demonstrated to inhibit the migration/invasion of NSCLC cells harboring different EGFR statuses via suppressing the Snail/Slug-mediated EMT. Mechanistic investigations showed that CD26/dipeptidyl peptidase IV (DPPIV) was downregulated by API following suppressive interplay of Akt and Snail/Slug signaling to modulate the EMT and the invasive ability of NSCLC cells. CD26 expression was positively correlated with the invasive abilities of NSCLC cells and a worse prognosis of lung cancer patients. Furthermore, we observed that patients with CD26high/Akthigh tumors had the shortest recurrence-free survival times. In vivo, API drastically reduced the growth and metastasis of A549 xenografts through targeting CD26. CONCLUSIONS CD26 may be a useful biomarker for predicting NSCLC progression. API effectively suppressed lung cancer progression by targeting the CD26-Akt-Snail/Slug signaling pathway.
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Affiliation(s)
- Jer-Hwa Chang
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Chao-Wen Cheng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan
| | - Yi-Chieh Yang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.,Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Wan-Shen Chen
- Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Wen-Yueh Hung
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan
| | - Jyh-Ming Chow
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Pai-Sheng Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Wei-Jiunn Lee
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, 111 Hsing Long Road, Section 3, Taipei, 11696, Taiwan. .,Department of Urology, School of Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan. .,Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, 111 Hsing Long Road, Section 3, Taipei, 11696, Taiwan. .,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
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7
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Chen XW, He ZX, Zhou ZW, Yang T, Zhang X, Yang YX, Duan W, Zhou SF. An update on the clinical pharmacology of the dipeptidyl peptidase 4 inhibitor alogliptin used for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2016. [PMID: 26218204 DOI: 10.1111/1440-1681.12469] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor that is a class of relatively new oral hypoglycaemic drugs used in patients with type 2 diabetes (T2DM), can be used as monotherapy or in combination with other anti-diabetic agents, including metformin, pioglitazone, sulfonylureas and insulin with a considerable therapeutic effect. Alogliptin exhibits favorable pharmacokinetic and pharmacodynamic profiles in humans. Alogliptin is mainly metabolized by cytochrome P450 (CYP2D6) and CYP3A4. Dose reduction is recommended for patients with moderate or worse renal impairment. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections and headache. Hypoglycaemia is seen in about 1.5% of the T2DM patients. Rare but severe adverse reactions such as acute pancreatitis, serious hypersensitivity including anaphylaxis, angioedema and severe cutaneous reactions such as Stevens-Johnson syndrome have been reported from post-marketing monitoring. Pharmacokinetic interactions have not been observed between alogliptin and other drugs including glyburide, metformin, pioglitazone, insulin and warfarin. The present review aimed to update the clinical information on pharmacodynamics, pharmacokinetics, adverse effects and drug interactions, and to discuss the future directions of alogliptin.
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Affiliation(s)
- Xiao-Wu Chen
- Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, China
| | - Zhi-Xu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA
| | - Xueji Zhang
- Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, China
| | - Yin-Xue Yang
- Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Vic., Australia
| | - Shu-Feng Zhou
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China.,Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
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8
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Beckenkamp A, Davies S, Willig JB, Buffon A. DPPIV/CD26: a tumor suppressor or a marker of malignancy? Tumour Biol 2016; 37:7059-73. [DOI: 10.1007/s13277-016-5005-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 02/25/2016] [Indexed: 12/12/2022] Open
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Choi HJ, Kim JY, Lim SC, Kim G, Yun HJ, Choi HS. Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression. Br J Pharmacol 2015; 172:5096-5109. [PMID: 26267432 PMCID: PMC4687806 DOI: 10.1111/bph.13274] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 06/19/2015] [Accepted: 07/10/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND PURPOSE Dipeptidyl peptidase 4 (DPP4) is an aminopeptidase that is widely expressed in different cell types. Recent studies suggested that DPP4 plays an important role in tumour progression in several human malignancies. Here we have examined the mechanisms by which up-regulation of DPP4 expression causes epithelial transformation and mammary tumourigenesis. EXPERIMENTAL APPROACH Expression of DPP4 and the peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1), and the cytotoxic effects of combined treatment with sitagliptin and juglone were investigated by immunohistochemistry, immunoblotting, real-time PCR, TUNEL and soft agar assays, using MCF7 cells. The effects of sitagliptin on tumour development in vivo were studied in the syngeneic 4T1 metastatic breast cancer model. KEY RESULTS Activity of the transcription factor E2F1 induced by EGF was enhanced by DPP4, thus increasing PIN1 expression. Furthermore, DPP4 enhanced MEK/ERK and JNK/c-Jun signalling induced by EGF, inducing AP-1 activity and epithelial cell transformation. In contrast, DPP4 silencing or DPP4 inhibition in MCF7 cells inhibited PIN1 expression via E2F1 activity induced by EGF, decreasing colony formation and inducing DNA fragmentation. In the syngeneic 4T1 metastatic breast cancer model, DPP4 overexpression increased tumour development, whereas treatment with sitagliptin and/or juglone suppressed it. Consistent with these observations, DPP4 levels were positively correlated with PIN1 expression in human breast cancer. CONCLUSIONS AND IMPLICATIONS DPP4 promoted EGF-induced epithelial cell transformation and mammary tumourigenesis via induction of PIN1 expression, suggesting that sitagliptin targeting of DPP4 could be a treatment strategy in patients with breast cancer.
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Affiliation(s)
- H J Choi
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - J Y Kim
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - S-C Lim
- Department of Pathology, School of Medicine, Chosun University, Gwangju, South Korea
| | - G Kim
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - H J Yun
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - H S Choi
- College of Pharmacy, Chosun University, Gwangju, South Korea
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10
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Prognostic relevance of stromal CD26 expression in rectal cancer after chemoradiotherapy. Int J Clin Oncol 2015; 21:350-358. [PMID: 26370256 DOI: 10.1007/s10147-015-0902-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 08/30/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND CD26 is a transmembrane glycoprotein whose role in various types of malignancies, along with the potential therapeutic and diagnostic targets, has been evaluated. Preoperative chemoradiotherapy (CRT) is an effective tool for local control of rectal cancer, but the rate of disease recurrence remains high. The aim of this study was to clarify the association between CD26 expression and rectal cancer after preoperative CRT. METHODS A total of 85 patients with rectal cancer who had undergone preoperative CRT were enrolled in this study. We investigated CD26 expression in residual tumors and the surrounding stromal tissue using immunohistochemistry. Additionally, stromal CD26 gene expression was assessed by real-time quantitative polymerase chain reaction. RESULTS Patients with high CD26 expression in cancer tissue more frequently had serosal invasion, vascular invasion, and a poor pathological response. High expression of CD26 in the tumor stroma was significantly correlated with histology and tumor recurrence. High CD26 expression in the stroma, but not the tumor itself, was significantly correlated with a poor prognosis. Patients expressing CD26 in the tumor stroma, based on transcriptional analysis, also had a significantly poorer prognosis than those without the expression. In multivariate analysis, lymph node metastasis and high stromal CD26 expression were identified as independent prognostic factors in patients with rectal cancer after neoadjuvant CRT. CONCLUSION Stromal CD26 expression after preoperative CRT was significantly associated with tumor recurrence and prognosis in rectal cancer patients. Our data suggest that stromal CD26 plays an important role and is a potential therapeutic target in tumor relapse.
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11
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Choi HJ, Kim JY, Lim SC, Kim G, Yun HJ, Choi HS. Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression. Br J Pharmacol 2015. [PMID: 26267432 DOI: 10.1111/bph.13274.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Dipeptidyl peptidase 4 (DPP4) is an aminopeptidase that is widely expressed in different cell types. Recent studies suggested that DPP4 plays an important role in tumour progression in several human malignancies. Here we have examined the mechanisms by which up-regulation of DPP4 expression causes epithelial transformation and mammary tumourigenesis. EXPERIMENTAL APPROACH Expression of DPP4 and the peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1), and the cytotoxic effects of combined treatment with sitagliptin and juglone were investigated by immunohistochemistry, immunoblotting, real-time PCR, TUNEL and soft agar assays, using MCF7 cells. The effects of sitagliptin on tumour development in vivo were studied in the syngeneic 4T1 metastatic breast cancer model. KEY RESULTS Activity of the transcription factor E2F1 induced by EGF was enhanced by DPP4, thus increasing PIN1 expression. Furthermore, DPP4 enhanced MEK/ERK and JNK/c-Jun signalling induced by EGF, inducing AP-1 activity and epithelial cell transformation. In contrast, DPP4 silencing or DPP4 inhibition in MCF7 cells inhibited PIN1 expression via E2F1 activity induced by EGF, decreasing colony formation and inducing DNA fragmentation. In the syngeneic 4T1 metastatic breast cancer model, DPP4 overexpression increased tumour development, whereas treatment with sitagliptin and/or juglone suppressed it. Consistent with these observations, DPP4 levels were positively correlated with PIN1 expression in human breast cancer. CONCLUSIONS AND IMPLICATIONS DPP4 promoted EGF-induced epithelial cell transformation and mammary tumourigenesis via induction of PIN1 expression, suggesting that sitagliptin targeting of DPP4 could be a treatment strategy in patients with breast cancer.
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Affiliation(s)
- H J Choi
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - J Y Kim
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - S-C Lim
- Department of Pathology, School of Medicine, Chosun University, Gwangju, South Korea
| | - G Kim
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - H J Yun
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - H S Choi
- College of Pharmacy, Chosun University, Gwangju, South Korea
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12
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Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice. Clin Exp Metastasis 2015; 32:677-87. [PMID: 26233333 DOI: 10.1007/s10585-015-9736-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 07/24/2015] [Indexed: 01/09/2023]
Abstract
Metastases rather than primary cancers determine nowadays the survival of patients. One of the most common primary malignancies is colorectal cancer and this type of tumor is characterized by a high tendency to spread metastases to the lung and liver. CD26/DPP4 is a transmembrane molecule with enzymatic functions which cleaves biologically active peptides. Recently, CD26/DPP4 has become the focus of cancer research and it was shown that CD26/DPP4-positive cancer cells display increased metastatic activity. Here, we tested if the CD26/DPP4-inhibitor Vildagliptin suppresses the development and growth of mouse colorectal lung metastases. This inhibitor of CD26/DPP4 was employed on mouse (C57BL/6) colorectal lung metastases, established by intravenous injection of the syngeneic cell line MC38. For mechanistic analysis, a subcutaneous tumor model was used. The treatment with Vildagliptin significantly suppressed both, the incidence and growth of lung metastases. Autophagy markers (LC3, p62, and ATF4) decreased, apoptosis increased (TUNEL, pH3/Ki-76), and the cell cycle regulator pCDC2 was inhibited. In conclusion, we here showed an anti-tumor effect of Vildagliptin via downregulation of autophagy resulting in increased apoptosis and modulation of the cell cycle. We therefore propose Vildagliptin for the evaluation as a new therapeutic approach for the treatment of colorectal cancer lung metastases.
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Varela-Calviño R, Cordero OJ. Stem and immune cells in colorectal primary tumour: Number and function of subsets may diagnose metastasis. World J Immunol 2015; 5:68-77. [DOI: 10.5411/wji.v5.i2.68] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 03/27/2015] [Accepted: 07/17/2015] [Indexed: 02/05/2023] Open
Abstract
An important percentage of colorectal cancer (CRC) patients will develop metastasis, mainly in the liver, even after a successful curative resection. This leads to a very high mortality rate if metastasis is not detected early on. Disseminated cancer cells develop from metastatic stem cells (MetSCs). Recent knowledge has accumulated about these cells particularly in CRC, so they may now be tracked from the removed primary tumour. This approach could be especially important in prognosis of metastasis because it is becoming clear that metastasis does not particularly rely on testable driver mutations. Among the many traits supporting an epigenetic amplification of cell survival and self-renewal mechanisms of MetSCs, the role of many immune cell populations present in tumour tissues is becoming clear. The amount of tumour-infiltrating lymphocytes (T, B and natural killer cells), dendritic cells and some regulatory populations have already shown prognostic value or to be correlated with disease-free survival time, mainly in immunohistochemistry studies of unique cell populations. Parallel analyses of these immune cell populations together with MetSCs in the primary tumour of patients, with later follow-up data of the patients, will define the usefulness of specific combinations of both immune and MetSCs cell populations. It is expected that these combinations, together to different biomarkers in the form of an immune score, may predict future tumour recurrences, metastases and/or mortality in CRC. It will also support the future design of improved immunotherapeutic approaches against metastasis.
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Cordero OJ, Varela-Calviño R, López-González T, Calviño-Sampedro C, Viñuela JE, Mouriño C, Hernández-Rodríguez Í, Rodríguez-López M, Aspe de la Iglesia B, Pego JM. CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis. PLoS One 2015; 10:e0131992. [PMID: 26177310 PMCID: PMC4503416 DOI: 10.1371/journal.pone.0131992] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 06/09/2015] [Indexed: 12/15/2022] Open
Abstract
We studied dipeptidyl peptidase IV (DPP-IV, CD26) expression in different T helper cells and serum soluble DPP-IV/sCD26 levels in rheumatoid arthritis (RA) patients, correlated these with disease activity score (DAS), and examined how they were affected by different therapies, conventional or biological (anti-TNF, anti-CD20 and anti-IL6R or Ig-CTLA4). The percentage of CD4+CD45R0+CD26- cells was greatly reduced in patients (up to 50%) when compared with healthy subjects. Three other subsets of CD4 cells, including a CD26high Th1-associated population, changed variably with therapies. Data from these subsets (frequency and staining density) significantly correlated with DAS28 or DAS28 components but different in each group of patients undergoing the different therapies. Th17 and Th22 subsets were implicated in RA as independent CCR4+ and CCR4- populations each, with distinct CD26 expression, and were targeted with varying efficiency by each therapy. Serum DPP-IV activity rather than sCD26 levels was lower in RA patients compared to healthy donors. DPP-IV and sCD26 serum levels were found related to specific T cell subsets but not to disease activity. We conclude that, according to their CD26 expression, different cell subsets could serve to monitor RA course, and an uncharacterized T helper CD26- subset, not targeted by therapies, should be monitored for early diagnosis.
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Affiliation(s)
- Oscar J. Cordero
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Santiago de Compostela, Spain
- * E-mail:
| | - Rubén Varela-Calviño
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Tania López-González
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Cristina Calviño-Sampedro
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Juan E. Viñuela
- Service of Immunology, University Hospital Complex of Santiago de Compostela, Santiago de Compostela, Spain
| | - Coral Mouriño
- Service of Rheumatology, University Hospital Complex of Vigo, Vigo, Spain
- IRIDIS (Investigation in Rheumatology and Immuno-mediated Diseases) Group, Instituto de Investigación Biomédica. Xerencia de Xestión Integrada-SERGAS, Vigo, Spain
| | | | - Marina Rodríguez-López
- Service of Rheumatology, University Hospital Complex of Vigo, Vigo, Spain
- IRIDIS (Investigation in Rheumatology and Immuno-mediated Diseases) Group, Instituto de Investigación Biomédica. Xerencia de Xestión Integrada-SERGAS, Vigo, Spain
| | | | - José María Pego
- Service of Rheumatology, University Hospital Complex of Vigo, Vigo, Spain
- IRIDIS (Investigation in Rheumatology and Immuno-mediated Diseases) Group, Instituto de Investigación Biomédica. Xerencia de Xestión Integrada-SERGAS, Vigo, Spain
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Oelkrug C, Sack U, Boldt A, Nascimento IC, Ulrich H, Fricke S. Antibody- and aptamer-strategies for GvHD prevention. J Cell Mol Med 2014; 19:11-20. [PMID: 25353670 PMCID: PMC4288345 DOI: 10.1111/jcmm.12416] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 08/01/2014] [Indexed: 02/06/2023] Open
Abstract
Prevention of Graft-versus-Host-Disease (GvHD) by preserved Graft-versus-Leukaemia (GvL) effect is one of the major obstacles following allogeneic haematopoietic stem cell transplantation. Currently used drugs are associated with side effects and were not able to separate GvHD from the GvL-effect because of general T-cell suppression. This review focuses on murine models for GvHD and currently available treatment options involving antibodies and applications for the therapeutic use of aptamers as well as strategies for targeting immune responses by allogenic antigens.
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Affiliation(s)
- Christopher Oelkrug
- Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany
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Havre PA, Dang LH, Ohnuma K, Iwata S, Morimoto C, Dang NH. CD26 expression on T-anaplastic large cell lymphoma (ALCL) line Karpas 299 is associated with increased expression of versican and MT1-MMP and enhanced adhesion. BMC Cancer 2013; 13:517. [PMID: 24180670 PMCID: PMC4228418 DOI: 10.1186/1471-2407-13-517] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 10/30/2013] [Indexed: 12/21/2022] Open
Abstract
Background CD26/dipeptidyl peptidase IV (DPPIV) is a multifunctional membrane protein with a key role in T-cell biology and also serves as a marker of aggressive cancers, including T-cell malignancies. Methods Versican expression was measured by real-time RT-PCR and Western blots. Gene silencing of versican in parental Karpas 299 cells was performed using transduction-ready viral particles. The effect of versican depletion on surface expression of MT1-MMP was monitored by flow cytometry and surface biotinylation. CD44 secretion/cleavage and ERK (1/2) activation was followed by Western blotting. Collagenase I activity was measured by a live cell assay and in vesicles using a liquid-phase assay. Adhesion to collagen I was quantified by an MTS assay. Results Versican expression was down-regulated in CD26-depleted Karpas 299 cells compared to the parental T-ALCL Karpas 299 cells. Knock down of versican in the parental Karpas 299 cells led to decreased MT1-MMP surface expression as well as decreased CD44 expression and secretion of the cleaved form of CD44. Parental Karpas 299 cells also exhibited higher collagenase I activity and greater adhesion to collagenase I than CD26-knockdown or versican-knockdown cells. ERK activation was also highest in parental Karpas 299 cells compared to CD26-knockdown or versican-knockdown clones. Conclusions Our data indicate that CD26 has a key role in cell adhesion and invasion, and potentially in tumorigenesis of T-cell lines, through its association with molecules and signal transduction pathways integral to these processes.
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Affiliation(s)
| | | | | | | | | | - Nam H Dang
- Division of Hematology/Oncology, University of Florida Shands Cancer Center, Gainesville, FL 32610, USA.
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Exendin-4 induces cell adhesion and differentiation and counteracts the invasive potential of human neuroblastoma cells. PLoS One 2013; 8:e71716. [PMID: 23990978 PMCID: PMC3750033 DOI: 10.1371/journal.pone.0071716] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 07/02/2013] [Indexed: 12/25/2022] Open
Abstract
Exendin-4 is a molecule currently used, in its synthetic form exenatide, for the treatment of type 2 diabetes mellitus. Exendin-4 binds and activates the Glucagon-Like Peptide-1 Receptor (GLP-1R), thus inducing insulin release. More recently, additional biological properties have been associated to molecules that belong to the GLP-1 family. For instance, Peptide YY and Vasoactive Intestinal Peptide have been found to affect cell adhesion and migration and our previous data have shown a considerable actin cytoskeleton rearrangement after exendin-4 treatment. However, no data are currently available on the effects of exendin-4 on tumor cell motility. The aim of this study was to investigate the effects of this molecule on cell adhesion, differentiation and migration in two neuroblastoma cell lines, SH-SY5Y and SK-N-AS. We first demonstrated, by Extra Cellular Matrix cell adhesion arrays, that exendin-4 increased cell adhesion, in particular on a vitronectin substrate. Subsequently, we found that this molecule induced a more differentiated phenotype, as assessed by i) the evaluation of neurite-like protrusions in 3D cell cultures, ii) the analysis of the expression of neuronal markers and iii) electrophysiological studies. Furthermore, we demonstrated that exendin-4 reduced cell migration and counteracted anchorage-independent growth in neuroblastoma cells. Overall, these data indicate for the first time that exendin-4 may have anti-tumoral properties.
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Abstract
CD26 is a 110-kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) activity that is expressed on various cell types and has many biological functions. An important aspect of CD26 biology is its peptidase activity and its functional and physical association with molecules with key roles in human immunological programs. CD26 role in immune regulation has been extensively characterized, with recent findings elucidating its link age with signaling pathways and structures involved in T cell activation a well as antigen-presenting cell-T cell interaction, being a marker of diseas behavior clinically as well as playing an important role in autoimmune pathogenesis and development. Through the use of various experimental approaches and agents to influence CD26/DPPIV expression and activity, such as anti-CD26 antibodies, CD26/DPPIV chemical inhibitors, siRNAs to inhibit CD26 expression, overexpressing CD26 transfectants, soluble CD26 molecules and proteomic approach, we have shown that CD26 interacts with structures with essential cellular functions in T cell responses. We will review emerging data that suggest CD26 may be an appropriate therapeutic target for the treatment of selected immune disorders.
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Affiliation(s)
- Kei Ohnuma
- Division of Rheumatology and Allergy, Research Hospital, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan
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