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Article: Downregulation of thymidylate synthase and E2F1 by arsenic trioxide in mesothelioma.

TitleDownregulation of thymidylate synthase and E2F1 by arsenic trioxide in mesothelioma.
Authors
Issue Date2015
Citation
International journal of oncology, 2015, v. 46 n. 1, p. 113-122 How to Cite?
AbstractMalignant pleural mesothelioma is a global health issue. Arsenic trioxide (ATO) has been shown to suppress thymidylate synthase (TYMS) in lung adenocarcinoma and colorectal cancer, and induce apoptosis in acute promyelocytic leukemia. With TYMS as a putative therapeutic target, the effect of ATO in mesothelioma was therefore studied. A panel of 5 mesothelioma cell lines was used to study the effect of ATO on cell viability, protein expression, mRNA expression and TYMS activity by MTT assay, western blot, qPCR and tritium-release assay, respectively. The knockdown of TYMS and E2F1 was performed with a specific siRNA. Phosphatidylserine externalization and mitochondrial membrane depolarization were measured by Annexin V and JC-1 staining respectively. The in vivo effect of ATO was studied using a nude mouse xenograft model. Application of ATO demonstrated anticancer effects in the cell line model with clinically achievable concentrations. Downregulation of TYMS protein (except H226 cells and 1.25 µM ATO in H2052 cells) and mRNA expression (H28 cells), pRB1 (H28 cells) and E2F1 and TYMS activity (except H226 cells) were also evident. E2F1 knockdown decreased cell viability more significantly than TYMS knockdown. In general, thymidine kinase 1, ribonucleotide reductase M1, c-myc and skp2 were downregulated by ATO. p-c-Jun was downregulated in H28 cells while upregulated in 211H cells. Phosphatidylserine externalization, mitochondrial membrane depolarization, downregulation of Bcl-2 and Bcl-xL, and upregulation of Bak and cleaved caspase-3 were observed. In the H226 xenograft model, the relative tumor growth was aborted, and E2F1 was downregulated while cleaved caspase-3 was elevated and localized to the nucleus in the ATO treatment group. ATO has potent antiproliferative and cytotoxic effects in mesothelioma in vitro and in vivo, partially mediated through E2F1 targeting (less effect through TYMS targeting). There is sound scientific evidence to support the clinical application of ATO in treatment of mesothelioma.
Persistent Identifierhttp://hdl.handle.net/10722/206796

 

DC FieldValueLanguage
dc.contributor.authorLam, SKen_US
dc.contributor.authorLi, Yen_US
dc.contributor.authorZheng, Cen_US
dc.contributor.authorHo, JCMen_US
dc.date.accessioned2014-12-02T09:29:15Z-
dc.date.available2014-12-02T09:29:15Z-
dc.date.issued2015en_US
dc.identifier.citationInternational journal of oncology, 2015, v. 46 n. 1, p. 113-122en_US
dc.identifier.urihttp://hdl.handle.net/10722/206796-
dc.description.abstractMalignant pleural mesothelioma is a global health issue. Arsenic trioxide (ATO) has been shown to suppress thymidylate synthase (TYMS) in lung adenocarcinoma and colorectal cancer, and induce apoptosis in acute promyelocytic leukemia. With TYMS as a putative therapeutic target, the effect of ATO in mesothelioma was therefore studied. A panel of 5 mesothelioma cell lines was used to study the effect of ATO on cell viability, protein expression, mRNA expression and TYMS activity by MTT assay, western blot, qPCR and tritium-release assay, respectively. The knockdown of TYMS and E2F1 was performed with a specific siRNA. Phosphatidylserine externalization and mitochondrial membrane depolarization were measured by Annexin V and JC-1 staining respectively. The in vivo effect of ATO was studied using a nude mouse xenograft model. Application of ATO demonstrated anticancer effects in the cell line model with clinically achievable concentrations. Downregulation of TYMS protein (except H226 cells and 1.25 µM ATO in H2052 cells) and mRNA expression (H28 cells), pRB1 (H28 cells) and E2F1 and TYMS activity (except H226 cells) were also evident. E2F1 knockdown decreased cell viability more significantly than TYMS knockdown. In general, thymidine kinase 1, ribonucleotide reductase M1, c-myc and skp2 were downregulated by ATO. p-c-Jun was downregulated in H28 cells while upregulated in 211H cells. Phosphatidylserine externalization, mitochondrial membrane depolarization, downregulation of Bcl-2 and Bcl-xL, and upregulation of Bak and cleaved caspase-3 were observed. In the H226 xenograft model, the relative tumor growth was aborted, and E2F1 was downregulated while cleaved caspase-3 was elevated and localized to the nucleus in the ATO treatment group. ATO has potent antiproliferative and cytotoxic effects in mesothelioma in vitro and in vivo, partially mediated through E2F1 targeting (less effect through TYMS targeting). There is sound scientific evidence to support the clinical application of ATO in treatment of mesothelioma.en_US
dc.languageengen_US
dc.relation.ispartofInternational journal of oncologyen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshAdenocarcinoma - drug therapy-
dc.subject.meshAntineoplastic Agents - pharmacology-
dc.subject.meshArsenicals - pharmacology-
dc.subject.meshLung Neoplasms - drug therapy-
dc.subject.meshOxides - pharmacology-
dc.subject.meshThymidylate Synthase - genetics-
dc.subject.meshThymidylate Synthase - metabolism-
dc.titleDownregulation of thymidylate synthase and E2F1 by arsenic trioxide in mesothelioma.en_US
dc.typeArticleen_US
dc.identifier.emailLam, SK: sklam77@hku.hken_US
dc.identifier.emailHo, JCM: jhocm@hku.hken_US
dc.identifier.authorityHo, JCM=rp00258en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3892/ijo.2014.2716en_US
dc.identifier.hkuros241542en_US
dc.identifier.volume46en_US
dc.identifier.spage113en_US
dc.identifier.epage122en_US

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