Molecular Basis for the Induction of an Angiogenesis Inhibitor, Thrombospondin-1, by 5-Fluorouracil

Zhao, Hongyan; Ooyama, Akio; Yamamoto, Masayuki; Ikeda, Ryuji; Haraguchi, Masanobu; Tabata, Satoshi; Furukawa, Tatsuhiko; Che, Xiaofang; Zhang, Shaoxuan; Oka, Toshinori; Fukushima, Masakazu; Nakagawa, Masayuki; Ono, Masahiro; Kuwano, Michihiko; Akiyama, Shin-ichi

doi:10.1158/0008-5472.can-07-6496

Cited by 39 publications

(28 citation statements)

References 34 publications

(32 reference statements)

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“…Therefore, 5-FU can be included in the growing list of antitumor agents such as cisplatin, ara-c or radiotherapy (Losa et al, 2003;Sanchez-Arevalo, et al, 2005;Lafarga et al, 2009), in which p38MAPK signaling pathway is a major determinant of the therapeutic effects. Previous reports indicated an activation of p38MAPK by 5-FU, but no relation to resistance was established (Elsea et al, 2008;Zhao et al, 2008). In this sense, our data in HaCaT, HCT116, HT-29, RKO, SW620 and LoVo cell lines, using pharmacological and genetic approaches, clearly demonstrate that the lack of p38MAPK activity promotes de novo and acquired resistance to 5-FU.…”

Section: Discussionsupporting

confidence: 55%

“…Interestingly, ara-c and gemcitabine are members of the same family of 5-FU (anti-metabolites), but no relationship between 5-FU resistance and p38MAPK has been reported. The only connection between 5-FU and p38MAPK is in the production of pro-inflammatory cytokines and thrombosposdin-1 in response to this drug (Elsea et al, 2008;Zhao et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

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RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

et al. 2011

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5-Fluorouracil (5-FU), together with other drugs such as oxaliplatin, is one of the most important pharmacological agents in the treatment of colorectal cancer. Although mitogen-activated protein kinases (MAPKs) have been extensively connected with resistance to platinum compounds, no role has been established in 5-FU resistance. Here we demonstrate that p38MAPK activation is a key determinant in the cellular response to 5-FU. Thus, inhibition of p38MAPKa by SB203580 compound or by short-hairpin RNA interference-specific knockdown correlates with a decrease in the 5-FU-associated apoptosis and chemical resistance in both HaCaT and HCT116 cells. Activation of p38MAPK by 5-FU was dependent on canonical MAP2K, MAPK kinase (MKK)-3 and MKK6. In addition, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) showed a redundancy of function for the final activation of p38MAPK. Resistance associated with p38MAPK inhibition correlates with an autophagic response that was mediated by a decrease in p53-driven apoptosis, without effect onto p53-dependent autophagy. Moreover, the results with colorectal cancer-derived cell lines with different p53 status and patterns of resistance to 5-FU suggest that de novo and acquired resistance was controlled by similar mechanisms. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the cellular response to 5-FU by controlling the balance between apoptosis and autophagy.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

et al. 2011

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“…Cyclophosphamide, one of the alkylating agents, that seriously damages DNA molecule was previously reported to induce TSP-1 (49). These findings together with our previous findings (23) suggest that TP is needed for the induction of Egr-1 and TSP-1 by 5-FU and the DNA damage by FdUMP caused the stress that activates p38 MAPK kinase pathway, and consequently induced Egr-1 and TSP-1 mRNA in the TPexpressing cells. Although further study is needed to elucidate whether Egr-1 and TSP-1 induction by 5-FU is implicated in the antitumor effect of 5-FU, our findings might be useful to develop new approaches for the treatment of TP-expressing tumors.…”

Section: The Effect Of LV and Tpi On The Induction Of Egr-1 And Tsp-1supporting

confidence: 75%

“…Recently, we found that 5-FU induced TSP-1 in human colon carcinoma KM12C cells (23). A transcription factor, Egr-1, was also induced by 5-FU and bound to the promoter of TSP-1, enhancing its transcription and the subsequent production of TSP-1 protein.…”

Section: The Effect Of LV and Tpi On The Induction Of Egr-1 And Tsp-1mentioning

confidence: 96%

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The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells

Akiyama¹

2010

Int J Oncol

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Abstract. Thymidine phosphorylase (TP) is an enzyme involved in reversible conversion of thymidine to thymine. TP is identical to an angiogenic factor, pletelet-derived endothelial cell growth factor (PD-ECGF) and the expression levels of TP in a variety of malignant tumors were higher than the adjacent non-neoplastic tissues. To investigate the molecular basis for the effect of TP on the metabolic process and the anticancer effect of 5-fluorouracil (5-FU), human gastric carcinoma AZ521 cells and epidermoid carcinoma KB cells were transfected with TP cDNA, and AZ521/TP and KB/ TP were cloned. AZ521/TP and KB/TP cells overexpressed TP and were more sensitive to 5-FU than the counterpart parental cells. TPI, a newly synthesized inhibitor for TP (Ki=2.36x10 -9 M), decreased the sensitivity to 5-FU of the TP expressing cells but not of the parental cells. 5-Formyltetrahydrofolate (leucovorin; LV) stabilized the complex of thymidylate synthase (TS) and 5-fluoro-deoxyuridinemonophosphate (FdUMP), increased the sensitivity to 5-FU of TP expressing AZ521 cells, but not of the parental cells. The levels of FdUMP in TP expressing cells were significantly higher than in parental cells and TPI considerably decreased FdUMP to the level comparable to that in the parental cells. 5-FU increased the expression of early growth response protein-1 (Egr-1) and an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in KB/TP cells but only slightly in KB/CV cells, if any. TPI attenuated the induction of Egr-1 and TSP-1 mRNA by 5-FU, while LV increased the expression of Egr-1 and TSP-1 mRNA in KB/TP cells. These findings demonstrate that the TP has a principal role in the production of FdUMP and the enhanced responses to 5-FU by leucovorin in TP-overexpressing KB and AZ521 cells, and FdUMP but not FUTP is implicated in the induction of Egr-1 and TSP-1 in KB cells. IntroductionThymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine, deoxyuridine, and their analogues to their respective bases and 2-deoxyribose-1-phosphate (1-3). It also catalyzes deoxyribosyltransfer from one deoxynucleotide to another base, to form a second deoxyuridine (4-6). Recent studies showed that TP is expressed in a wide variety of solid tumors (7-13), but the role of TP in tumor proliferation was unknown. We have found that TP is identical to an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), and the enzymatic activity of TP is need for the angiogenesis by TP (14-16). TP is also considered to activate some pyrimidine antimetabolites (17-19). 5-Fluorouracil (5-FU) was developed as a potential anti-tumor drug (20), and reportedly activated through three alternative routes. It may be converted to FUMP either directly by orotate phosphoribosyltranferase or by the sequential actions of uridine phosphorylase and uridine kinase. FUMP may be converted to FUDP and then to FUTP, INTERNATIONAL JOURNAL OF ONCOLOGY 36: 1193-1200, 2010 The role of thymidine phosphorylase in the induction of early growth response protein-1...

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The Biomodulatory Capacities of Low-Dose Metronomic Chemotherapy: Complex Modulation of the Tumor Microenvironment

Emmenegger

Chow

Bocci

2010

From Molecular to Modular Tumor Therapy

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Molecular Basis for the Induction of an Angiogenesis Inhibitor, Thrombospondin-1, by 5-Fluorouracil

Cited by 39 publications

References 34 publications

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells

The Biomodulatory Capacities of Low-Dose Metronomic Chemotherapy: Complex Modulation of the Tumor Microenvironment

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