Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway

Tan, Ernest Y.; Richard, Cynthia L.; Zhang, Hong; Blay, Jonathan

doi:10.1152/ajpcell.00238.2005

Cited by 33 publications

(19 citation statements)

References 83 publications

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“…We focused on the human colorectal cancer cell line HT-29, which has been used for many of our mechanistic studies on CD26/DPPIV [30,46]. We initially treated HT-29 cells with a single 50 lM dose of flavonoid for 48 h. Using a radioimmunoassay that selectively detects cell-surface CD26 protein [30], CD26 was consistently found to be up-regulated by both apigenin and genistein but not by kaempferol (Fig.…”

Section: Resultsmentioning

confidence: 99%

The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells

Lefort

Blay

2011

Clin Exp Metastasis

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There is accumulating evidence that secondary plant metabolites such as flavonoids may have anti-cancer properties, and yet the molecular pathways that lead to alterations in cancer cell behaviour remain unclear. We investigated the possible actions of apigenin, a flavone present in leafy vegetables like parsley, on the levels of CD26 in carcinoma cells. CD26 is a multifunctional cell-surface protein that through its associated dipeptidyl peptidase (DPPIV) and ecto-adenosine deaminase (eADA) enzyme activities is able to suppress pathways involved in tumour metastasis. CD26 is down-regulated in various cancers including colorectal carcinoma. Apigenin substantially up-regulated cell-surface CD26 on HT-29 and HRT-18 human colorectal cancer cells. Levels of CD26 protein, along with its associated DPPIV enzyme activity, capacity to bind eADA, and ability to link cells to fibronectin, were increased with a maximum after 24-48 h. Elevation of CD26 occurred at concentrations that were at least 10-fold less than those shown to affect cell growth, and 100-fold below those that could affect cell viability. Furthermore, the CD26 effect was enhanced when apigenin was paired with chemotherapeutic agents utilized in the treatment of advanced colorectal cancer including irinotecan, 5-fluorouracil and oxaliplatin. For irinotecan, apigenin caused a 4-fold increase in the potency of the drug. These results demonstrate that apigenin can increase the cellular levels of CD26 and its multiple functions, and may oppose the predicted effect of decreased DPPIV and eADA activities on carcinoma cells, which is to facilitate tumour growth and metastasis.

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Section: Resultsmentioning

confidence: 99%

The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells

Lefort

Blay

2011

Clin Exp Metastasis

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“…One such mechanism is the subject of the article by Blay and co-workers (16), featured on page C433 of this issue. These investigators and others have noted in previous studies that the cell surface protein, CD26, is downregulated in many cancers.…”

Section: Cd26 Expression In Tumorsmentioning

confidence: 98%

Adenosine metabolism and cancer. Focus on “Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatases and reducing ERK1/2 activity via a novel pathway”

Linden

2006

American Journal of Physiology-Cell Physiology

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ADENOSINE FACILITATES tumor survival by a variety of mechanisms. In this issue, Tan et al. (Ref. 16; see p. C433 of this issue) describe a signaling cascade by which adenosine downregulates the cell surface protein CD26 on HT-20 colorectal carcinoma cells. Because CD26 binds extracellular soluble adenosine deaminase (ADA) to the cell surface, this downregulation is expected to increase adenosine concentration in the microenvironment of the tumor cell membrane. This is one of several mechanisms by which tumors facilitate their own survival by influencing adenine nucleotide and adenosine metabolism and signaling.Adenosine accumulates in solid tumors and stimulates tumor growth and tumor angiogenesis while imparting tumor resistance to the immune system (15). Part of this resistance is due to adenosine signaling through A 2A and possibly A 2B adenosine receptors to inhibit the activation of macrophages (9, 10) and lymphocytes (6). Imiquimod, an immune system activator with anti-tumor activity, has recently been shown to block A 2A receptors (14). This is consistent with the notion that adenosine in tumors suppresses the immune system. CD26 EXPRESSION IN TUMORSWhile adenosine is generated as a result of hypoxia and cell necrosis in the core of tumors, there is emerging evidence that some tumors modify purine metabolism to facilitate production or retard degradation of adenosine. One such mechanism is the subject of the article by Blay and co-workers (16), featured on page C433 of this issue. These investigators and others have noted in previous studies that the cell surface protein, CD26, is downregulated in many cancers. In human (but not murine) cells CD26 serves as a binding protein for ecto-ADA, and, by localizing ADA to the cell surface, facilitates adenosine metabolism to inosine. Downregulating CD26 likely results in increased adenosine, especially near the cell surface. This could contribute to immune suppression in the tumor environment (Fig. 1). In their study, Blay and coworkers show that high levels of adenosine downregulate CD26 on the surface of HT-29 colorectal carcinoma cells, possibly resulting in the following positive feedback mechanism: decreased adenosine degradation 3 increased adenosine 3 decreased CD26 expression 3 decreased adenosine degradation. The downregulation of CD26 in tumor cells is correlated with increased protein tyrosine phosphatase and ERK activity and a decrease in CD26 transcription, although it is not clear that all of these effects are causally related. The downregulation of CD26 in response to adenosine is not significantly blocked by adenosine receptor antagonists, suggesting that CD26 regulation may not be mediated by G protein-coupled adenosine receptors, although it is possible that adenosine levels become high enough to overcome competitive receptor blockade. ADENINE NUCLEOTIDE METABOLISM IN TUMOR HOSTS AND IN TUMORSThe downregulation of CD26 is one of several means by which cancer cells may elevate extracellular adenosine to promote tumor angiogenesis and escape immun...

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“…The monomeric form of DPP4 has no enzyme activity. Because DPP4 as a homodimer is a fully active enzyme, activity regulation has to be realised at the level of gene expression, protein synthesis and substrate selection [8][9][10][11][14][15][16][17]. Interferons and retinoic acid upregulated DPP4 gene expression through the signalling pathway involving the signal transducer and activator of transcription Stat1 , which binds consensus sequences known as GAS motifs, to activate CD26 gene promoters [14].…”

Section: Catalytic Activitymentioning

confidence: 99%

“…Adenosine downregulates DPP4 by modulating mRNA expression. This cellular response to adenosine is not mediated through G-protein-coupled adenosine receptors, but it occurs through an increase in tyrosine protein phosphatase activity to cause a decrease in the tyrosine phosphorylation of extracellular signal-regulated kinase (ERK)1/2 mitogenactivated protein kinase (MAPK) that leads to the alteration in DPP4 mRNA [16]. DPP4 has been suggested as a novel marker of hypoxia inducible factor-1 (HIF-1 ) induction [17].…”

Section: Catalytic Activitymentioning

confidence: 99%

Dipeptidyl Peptidase-4 (CD26): Knowing the Function before Inhibiting the Enzyme

Matteucci

Giampietro

2009

CMC

174

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Dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) or T-cell activation antigen CD26 (EC 3.4.14.5.) is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. The enzyme is a type II transmembrane glycoprotein, expressed on the surface of many cell types, whose physiological functions are largely unknown. Protein dimerisation should be required for catalytic activity and glycosylation of the enzyme could impact on its physiological functions. The dimeric glycoprotein ADCP has been found linked to adenosine deaminase (ADA) whose relationship with lymphocyte maturation-differentiation is well-established. Since implicated in the regulation of the biological activity of hormones and chemokines, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, DPP4 inhibition offers a new potential therapeutic approach for type 2 diabetes mellitus, as monotherapy and adjunct therapy to other oral agents. The clinical use of presently available orally active inhibitors of DPP4, however, has been associated with side effects that have been in part attributed to the inhibition of related serine proteases, such as DPP8 and DPP9. Indeed, it is noteworthy that CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder. All-cause infections were increased after sitagliptin treatment. It is noteworthy that the effects of DPP4 inhibition on the immune system have not been extensively investigated. So far, only routine laboratory safety variables have been measured in published randomised controlled trials. The review summarises present knowledge in the field and suggests some potential directions of future research.

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Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway

Abstract: downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway.

Cited by 33 publications

References 83 publications

The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells

The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells

Adenosine metabolism and cancer. Focus on “Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatases and reducing ERK1/2 activity via a novel pathway”

Dipeptidyl Peptidase-4 (CD26): Knowing the Function before Inhibiting the Enzyme

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