Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy

Liekens, Sandra; Bronckaers, Annelies; Pérez‐Pérez, María‐Jesús; Balzarini, Jan

doi:10.1016/j.bcp.2007.05.008

Cited by 72 publications

(62 citation statements)

References 92 publications

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“…However, future studies will be required to confirm the clinical significance of this proposed ERK-dependent translocation mechanism. Given that overexpression of TP in NPC is associated with poor prognosis (Chen et al, 2008), TP may be seen as a potential drug target for treatment of NPC, as previously shown for metastatic colorectal and breast carcinoma (Liekens et al, 2007). Accordingly, clarification of the exact mechanism of TP expression may improve patient stratification and facilitate the development of novel therapeutic strategies.…”

Section: Discussionmentioning

confidence: 92%

“…TP acts as an angiogenic factor and mediates inhibition of tumor cell apoptosis, thereby contributing to tumor progression (reviewed in Liekens et al, 2007). Cytoplasmic accumulation of hnRNP K is significantly associated with high TP expression in NPC, and high levels of both proteins are correlated with shorter survival and distant metastasis in NPC patients (Chen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Additionally, both angiogenic and chemotactic properties have been attributed to TP, which has been shown to inhibit tumor cell apoptosis (reviewed in Liekens et al, 2007). TP is overexpressed in various cancers, including NPC, and its expression levels have been shown to have prognostic value (Liekens et al, 2007;Chen et al, 2008). The increased enzymatic activity of TP in cancer cells is utilized to activate capecitabine for treatment of metastatic colorectal and breast carcinomas (Liekens et al, 2007), and to increase the sensitivity of NPC cells to the capecitabine intermediate prodrug, 5 0 -DFUR (Chen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Liu

et al. 2009

Oncogene

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The cytoplasmic level of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is significantly correlated with the elevated expression of thymidine phosphorylase (TP), and high levels of both proteins are predictive of a poor prognosis in nasopharyngeal carcinoma (NPC). We herein show that TP is highly induced by serum deprivation in NPC cells, and that this is due to an increase in the halflife of the TP mRNA, as shown by nuclear run-on and actinomycin D assays. We further show that the CU-rich element of the TP mRNA directly interacts with hnRNP K, as demonstrated by immunoprecipitation RT-PCR assays, and the nucleus-to-cytoplasm translocation of hnRNP K. Blockade of hnRNP K expression reduces TP expression, suggesting that hnRNP K acts in the upregulation of TP. Mechanistically, both MEK inhibitor and the hnRNP K ERK-phosphoacceptor-site mutant decrease cytoplasmic accumulation of hnRNP K, suggesting that ERK-dependent phosphorylation is critical for TP induction. Furthermore, we found that hnRNP Kmediated TP induction allows NPC cells to resist hypoxia-induced apoptosis. Our results collectively establish the regulation and role of ERK-mediated cytoplasmic accumulation of hnRNP K as an upstream modulator of TP, suggesting that hnRNP K may be an attractive candidate as a future therapeutic target for cancer.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Liu

et al. 2009

Oncogene

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“…The platelet derived endothelial cell growth factor (PD-ECGF) or thymidine phosphorylase (TP) is often overexpressed in human cancers, which has been related to a higher microvessel density, a higher tumor stage and the induction of metastasis [1,2,3,4]. In various in vitro studies, TP had a chemotactic effect on endothelial cells [5,6,7,8].…”

Section: Introductionmentioning

confidence: 99%

Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells

Bijnsdorp

Azijli

Jansen

et al. 2010

Biochemical Pharmacology

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Rcl is a novel ETV1/ER81 target gene upregulated in breast tumors

Shin

Bosc

Ingle

et al. 2008

J of Cellular Biochemistry

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ETV1 (ER81) is a transcription factor that can be activated by HER2/Neu, a proto-oncoprotein often overexpressed in metastatic breast tumors. Here, we demonstrate that ETV1 downregulation suppresses proliferation of HER2/Neu-positive MDA-MB-231 breast cancer cells in vitro and tumor formation in vivo, proving for the first time the existence of a critical role of ETV1 in breast cancer cell physiology. A screen for novel ETV1 target genes hinted at Rcl, an enzyme involved in nucleotide metabolism. To characterize the human Rcl gene, we cloned its promoter and found that ETV1 and HER2/Neu cooperated in activating the Rcl promoter, whereas a dominant-negative ETV1 molecule suppressed the Rcl promoter. Moreover, ETV1 and HER2/Neu synergized to upregulate the endogenous Rcl gene. ETV1 also bound to the Rcl promoter in vivo, indicating that Rcl is a bona fide target gene of ETV1. Hybridization of Rcl cDNA to a breast cancer array revealed that Rcl is overexpressed in approximately 40% of all breast tumors. Importantly, its expression significantly escalates with increasing tumor grade, strongly implicating that Rcl contributes to breast tumorigenesis. Since joint overexpression of Rcl with vascular endothelial growth factor, another target gene of ETV1, has been shown to induce tumor formation, Rcl may be one crucial effector of ETV1 and HER2/Neu in breast tumors. Furthermore, given its expression pattern and enzymatic function in nucleotide metabolism, Rcl presents itself as a novel target in breast cancer therapy via modulation of its activity by small molecule drugs.

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Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy

Cited by 72 publications

References 92 publications

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells

Rcl is a novel ETV1/ER81 target gene upregulated in breast tumors

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