Prevention of Hypoxia-Induced Apoptosis by the Angiogenic Factor Thymidine Phosphorylase

Kitazono, Masaki; Takebayashi, Yuji; Ishitsuka, Kenji; Takao, Sonshin; Tani, Akira; Furukawa, Tatsuhiko; Miyadera, Kazutaka; Yamada, Yuji; Aikou, Takashi; Akiyama, Shin–ichi

doi:10.1006/bbrc.1998.9852

Cited by 106 publications

(78 citation statements)

References 23 publications

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“…Increased tumor cell resistance to hypoxia may therefore contribute to tumor progression. TP has been shown to be a survival factor capable of protecting cells from hypoxia-induced apoptosis (Kitazono et al, 1998;Ikeda et al, 2006), and it has been significantly associated with cytoplasmic accumulation of hnRNP K and poorer survival in patients with NPC (Chen et al, 2008). Accordingly, we herein propose that hnRNP K participates in tumorigenesis through TP induction, further contributing to tumor cell survival under stress conditions (hypoxia).…”

Section: Discussionmentioning

confidence: 79%

“…Previous studies have suggested that the catalytic product of TP, 2-deoxy-D-ribose, prevents hypoxiainduced apoptosis (Kitazono et al, 1998;Ikeda et al, 2006). To determine whether overexpression of TP is beneficial for the survival of cancer cells undergoing hypoxia, we incubated NPC-TW02 cells stably expressing high levels of recombinant TP in 2% O 2 for 72 h, thereby mimicking hypoxic conditions.…”

Section: Hnrnp K and Tp Prevent Hypoxia-induced Apoptosis In Npc Cellsmentioning

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: 79%

Section: Hnrnp K and Tp Prevent Hypoxia-induced Apoptosis In Npc Cellsmentioning

confidence: 99%

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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“…It is therefore possible that different tumour cell lines may demonstrate considerable variation when studying the effects of TP activity upon HIF-1a induction. It has been known for several years that 2-deoxy-D-ribose reduces hypoxia-induced apoptosis in the cell lines KB-3-1 and HL-60 (Kitazono et al, 1998) (Ikeda et al, 2002). It would therefore be of future interest to determine whether TP activity promotes or represses hypoxia-induced apoptosis in our bladder carcinoma cell line.…”

Section: Discussionmentioning

confidence: 99%

Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma

et al. 2005

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Elevated thymidine phosphorylase has been shown to correlate with increased angiogenesis and poor prognosis in many cancers including transitional cell carcinoma of the bladder. In vitro studies have demonstrated that thymidine phosphorylase activity causes cellular oxidative stress and increases secretion of vascular endothelial growth factor. In this study, we show that thymidine phosphorylase activity also augments levels of the hypoxia-inducible factor-1a during in vitro hypoxia, and that thymidine phosphorylase activity and hypoxia act in concert to increase vascular endothelial growth factor (VEGF) secretion. We also demonstrate that thymidine phosphorylase overexpression confers tumorigenicity on an orthotopically implanted transitional cell carcinoma cell line. Administration of the antioxidant N-acetylcysteine together with a blocking anti-VEGF antibody abrogates the increase in tumorigenicity. Our results support the increased efficacy of combination approaches to antiangiogenic therapy.

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“…Deoxyribose-1-phosphate has been reported to be the main angiogenic factor related to dThdPase. 24 Two possible reasons could be speculated for lack of correlation between UPase and dThdPase. First, the enzyme levels may be related to the levels of the thymidine and uridine pools, which may differ independently from tumor to tumor in breast carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Expression of uridine and thymidine phosphorylase genes in human breast carcinoma

Kanzaki

Takebayashi

Bando

et al. 2001

Intl Journal of Cancer

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Uridine phosphorylase (UPase) and an angiogenic enzyme, thymidine phosphorylase (dThdPase) are involved in degradation of the pyrimidine nucleosides through phosphorolysis. The expression levels of UPase and dThdPase are higher in human solid tumors including breast carcinomas than in normal tissues. To clarify the correlation between the expression levels of UPase and dThdPase genes and the clinicopathological factors, mRNA levels of these enzymes were examined by RT-PCR in 43 breast carcinomas. UPase gene expression was not correlated with dThdPase gene expression (regression coefficient R ‫؍‬ 0.032). Although the expression level of the dThdPase gene was correlated with angiogenesis, detected by immunostaining endothelial cells (R ‫؍‬ 0.66), that of UPase gene was not (R ‫؍‬ 0.044). These results suggest that UPase does not have a strong angiogenic activity. The UPase gene expression levels in tumors of patients who relapsed were significantly higher than in those from patients who did not (p ‫؍‬ 0.039). Although the expression levels of neither UPase or dThdPase were associated with age, pT, pN, pM, estrogen or progesterone receptor positivity, the patients with the higher levels of UPase gene expression had worse survival (p ‫؍‬ 0.0038) than those with lower levels. In contrast, the expression of dThdPase gene was not related to relapse or survival of these patients with breast carcinoma. Our findings suggest that the expression level of UPase gene may be an independent prognostic marker in human breast carcinoma.

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Prevention of Hypoxia-Induced Apoptosis by the Angiogenic Factor Thymidine Phosphorylase

Cited by 106 publications

References 23 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

Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma

Expression of uridine and thymidine phosphorylase genes in human breast carcinoma

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