Thymidine Phosphorylase: A Two-Face Janus in Anticancer Chemotherapy

Focher, Federico; Spadari, Silvio

doi:10.2174/1568009013334232

Cited by 69 publications

(55 citation statements)

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“…88,89 TYPH (TP, ECGF1) is involved in thymidine metabolism and homeostasis by catalyzing thymidine dephosphorylation with broad substrate specificity. 90 TYPH is elevated in various tumors and plays a role in tumor progression and angiogenesis. 91 TYPH is highly expressed in microvessels of CIN and SCC and appears to be involved in angiogenesis in CIN.…”

Section: Discussionmentioning

confidence: 99%

Proteomic identification of potential biomarkers for cervical squamous cell carcinoma and human papillomavirus infection

Song

Tulake

et al. 2017

Tumour Biol.

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It is known that high-risk human papillomavirus infection is the main etiological factor in cervical carcinogenesis. However, human papillomavirus screening is not sufficient for early diagnosis. In this study, we aimed to identify potential biomarkers common to cervical carcinoma and human papillomavirus infection by proteomics for human papillomavirus-based early diagnosis and prognosis. To this end, we collected 76 cases of fresh cervical tissues and 116 cases of paraffin-embedded tissue slices, diagnosed as cervical squamous cell carcinoma, cervical intraepithelial neoplasia II-III, or normal cervix from ethnic Uighur and Han women. Human papillomavirus infection by eight oncogenic human papillomavirus types was detected in tissue DNA samples using a quantitative polymerase chain reaction. The protein profile of cervical specimens from human papillomavirus 16-positive squamous cell carcinoma and human papillomavirus-negative normal controls was analyzed by proteomics and bioinformatics. The expression of candidate proteins was further determined by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. We identified 67 proteins that were differentially expressed in human papillomavirus 16-positive squamous cell carcinoma compared to normal cervix. The quantitative reverse transcriptase-polymerase chain reaction analysis verified the upregulation of ASAH1, PCBP2, DDX5, MCM5, TAGLN2, hnRNPA1, ENO1, TYPH, CYC, and MCM4 in squamous cell carcinoma compared to normal cervix (p < 0.05). In addition, the transcription of PCBP2, MCM5, hnRNPA1, TYPH, and CYC was also significantly increased in cervical intraepithelial neoplasia II-III compared to normal cervix. Immunohistochemistry staining further confirmed the overexpression of PCBP2, hnRNPA1, ASAH1, and DDX5 in squamous cell carcinoma and cervical intraepithelial neoplasia II-III compared to normal controls (p < 0.05). Our data suggest that the expression of ASAH1, PCBP2, DDX5, and hnRNPA1, and possibly MCM4, MCM5, CYC, ENO1, and TYPH, is upregulated during cervical carcinogenesis and potentially associated with human papillomavirus infection. Further validation studies of the profile will contribute to establishing auxiliary diagnostic markers for human papillomavirus-based cancer prognosis. KeywordsCervical carcinoma, isobaric tags for relative and absolute quantitation, proteomics, human papillomavirus infection, cervical specimen Date

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Section: Discussionmentioning

confidence: 99%

Proteomic identification of potential biomarkers for cervical squamous cell carcinoma and human papillomavirus infection

Song

Tulake

et al. 2017

Tumour Biol.

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“…Subsequently, mutations in the gene encoding TP were identified as the cause of MNGIE (Nishino et al 1999). The enzyme TP (EC 2.4.2.4) is also known as gliostatin or endothelial cell growth factor 1 (platelet-derived), whose acronym gives name to the gene (gene ECGF1) (Hagiwara et al 1991;Asai et al 1992;Usuki et al 1992;Brown and Bicknell 1998;Focher and Spadari 2001). As shown in Fig.…”

Section: Genetic Origin Of Mngiementioning

confidence: 99%

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Biochemical Features and Therapeutic Approaches

et al. 2007

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Over the last 15 years, important research has expanded our knowledge of the clinical, molecular genetic, and biochemical features of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The characterization of mitochondrial involvement in this disorder and the seminal determination of its genetic cause, have opened new possibilities for more detailed and deeper studies on the pathomechanisms in this progressive and fatal disease. It has been established that MNGIE is caused by mutations in the gene encoding thymidine phosphorylase (TP), which lead to absolute or nearly complete loss of its catalytic activity, producing systemic accumulations of its substrates, thymidine (dThd) and deoxyuridine (dUrd). Findings obtained from in vitro and in vivo studies indicate that the biochemical imbalances specifically impair mitochondrial DNA (mtDNA) replication, repair, or both leading to mitochondrial dysfunction. We have proposed that therapy for MNGIE should be aimed at reducing the concentrations of these toxic nucleosides to normal or nearly normal levels. The first treatment, allogeneic stem-cell transplantation (alloSCT) reported in 2006, produced a nearly full biochemical correction of the dThd and dUrd imbalances in blood. Clinical follow-up of this and other patients receiving alloSCT is necessary to determine whether this and other therapies based on a permanent restoration of TP will be effective treatment for MNGIE.

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“…[57][58][59][60][61] Subsequently, it was discovered that this molecule is identical to thymidine phosphorylase (TP), an enzyme involved with intracellular thymidine metabolism and homeostasis. PD-ECGF/TP is also gliostatin (GS), a protein purified from human neurofibroma having neurotrophic actions and effects on glial differentiation.…”

Section: Intracinesmentioning

confidence: 99%

“…59 The angiogenic activity of PD-ECGF/TP is dependent on its enzymatic activity. 58 Nonetheless, it is an intracellular regulator of metabolism and an extracellular signaling protein. Like AMF and angiogenin, PD-ECGF/TP is a secreted enzyme that stimulates target cell migration and is angiogenic.…”

Section: Intracinesmentioning

confidence: 99%

Intracellular Renin and the Nature of Intracrine Enzymes

Ré

2003

Hypertension

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Abstract-Recently, the binding of renin and prorenin to cellular receptors with the subsequent generation of second messengers and the production of physiological effects has been demonstrated. In addition, the internalization of prorenin by target cells has been associated with increased cellular synthesis of angiotensin and cardiac pathology. Also, a renin transcript lacking the sequences encoding a secretory signal has been reported, and this transcript appears to produce a renin that acts in the cell that synthesized it. Some years ago, we coined the term intracrine for a peptide hormone or factor that acts in the intracellular space either after internalization or retention in its cell of synthesis. Thus defined, a wide variety of peptides display intracrine functionality, including hormones, growth factors, transcription factors, and enzymes. For example, considerable evidence indicates that angiotensin II is an intracrine. Also, general principles of intracrine functionality have been developed. Thus, recent evidence demonstrates that the prorenin/renin molecule is an intracrine enzyme. Here, the actions of intracrine enzymes (angiogenin, phosphoglucose isomerase, phospholipase A2, granzyme A and B, thioredoxin, platelet-derived endothelial growth factor, and serine protease inhibitors) are reviewed. Key Words: renin Ⅲ platelet-derived growth factor Ⅲ enzymes Ⅲ angiotensin II Ⅲ phospholipases R enin gene expression leads to the synthesis of prorenin in the juxtaglomerular cells of the kidney, activation and secretion of renin by these cells, the generation of angiotensin I by renin enzymatic activity, and the subsequent generation of angiotensin II either in the plasma or tissues. However, renin, angiotensin I, and angiotensin II can also be taken up by tissues with subsequent enzymatic conversions occurring locally. Moreover, there is considerable evidence, both in animal models and in humans, in favor of the local synthesis of each of the components of the renin-angiotensin system (RAS) in various tissues leading to locally determined angiotensin generation. 1 In addition to evidence indicating local synthesis and uptake in tissues of RAS components, there is growing evidence to indicate the uptake and synthesis of components of the RAS by individual cells, thereby suggesting a new arena for the action of this physiological system. 2 Important among these new observations are studies demonstrating that (1) prorenin and renin can bind to specific cellular receptors with the generation of physiological effects, (2) prorenin, and to a lesser extent, renin, can be internalized by cells whereupon angiotensin II is produced, and (3) there exists a renin transcript in some cells that encodes a renin that is expected to be synthesized as an active, as opposed to a prorenin, and that is expected to remain in the cell because it lacks the sequence encoding the secretory signal piece (renin exon 1A). 2-13 These observations not only reveal prorenin and renin to be hormones in their own right, they suggest that pro...

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Thymidine Phosphorylase: A Two-Face Janus in Anticancer Chemotherapy

Cited by 69 publications

References 0 publications

Proteomic identification of potential biomarkers for cervical squamous cell carcinoma and human papillomavirus infection

Proteomic identification of potential biomarkers for cervical squamous cell carcinoma and human papillomavirus infection

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Biochemical Features and Therapeutic Approaches

Intracellular Renin and the Nature of Intracrine Enzymes

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