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Conference Paper: Combination effect of arsenic trioxide and FGFR inhibitor through downregulation of FGFR, Akt and Erk in squamous cell lung carcinoma

TitleCombination effect of arsenic trioxide and FGFR inhibitor through downregulation of FGFR, Akt and Erk in squamous cell lung carcinoma
Authors
Issue Date2014
Citation
The 21st Hong Kong International Cancer Congress (HKICC 2014), Hong Kong, 21 November 2014. How to Cite?
AbstractBackground: Lung cancer is the top cancer killer. Squamous cell lung carcinoma (SCC) represents the second most common histologic subtype of lung cancer. Arsenic trioxide (ATO) has been demonstrated to inhibit tumor growth in lung adenocarcinoma and initiate apoptosis in acute promyelocytic leukemia. Fibroblast growth factor (FGF) receptor (FGFR) amplification is shown in some SCC. FGFR inhibitor (e.g. PD173074) has been developed to inhibit FGFR. Methods: The combination effect of ATO and PD173074 was studied using a cell line with FGFR amplification: SK-MES-1. The effect of ATO and/or PD173074 on cell viability and protein expression was studied by MTT assay and Western blot respectively. Cell cycle arrest, phosphatidylserine externalization and mitochondrial membrane depolarization were monitored by flow cytometry. FGFR knockdown was performed with siRNA targeting FGFR. Proteasome inhibitor (MG-132) was used to study the degradation mechanism. The in vivo effect of ATO and/or PD173074 was investigated with a nude mice xenograft model. Results: Combination of ATO and PD173074 reduced cell viability along with increased sub-G1 population, phosphatidylserine externalization and mitochondrial membrane depolarization more significantly than single drug alone. In general, downregulation of FGFR, p-Akt, Akt, p-Src, Src, p-c-Raf, c-Raf, Erk, Bcl-2 and survivin as well as upregulation of p-Erk and cleaved PARP were observed upon ATO and/or PD treatment with or without FGF. MG-132 reversed the degradation of Akt, Src, c-Raf and Erk induced by ATO/PD, but not FGFR, which disclosed proteasome degradation system was involved. Downregulation of FGFR, Akt, Src, c-Raf and Erk as well as cleaved PARP elevation induced by ATO and/or PD were confirmed in vivo. Conclusion: Massive protein degradation (FGFR, Akt, Src, c-Raf and Erk) was induced by ATO and/or PD173074 treatment mainly mediated by activation of proteasome degradation system in SCC cell line SK-MES-1 in vitro and in vivo.
DescriptionCongress Theme: Translating Discoveries into Prevention and Cures
Persistent Identifierhttp://hdl.handle.net/10722/206848

 

DC FieldValueLanguage
dc.contributor.authorLam, SKen_US
dc.contributor.authorLi, Yen_US
dc.contributor.authorZheng, Cen_US
dc.contributor.authorLeung, LLen_US
dc.contributor.authorHo, JCMen_US
dc.date.accessioned2014-12-02T10:28:28Z-
dc.date.available2014-12-02T10:28:28Z-
dc.date.issued2014en_US
dc.identifier.citationThe 21st Hong Kong International Cancer Congress (HKICC 2014), Hong Kong, 21 November 2014.en_US
dc.identifier.urihttp://hdl.handle.net/10722/206848-
dc.descriptionCongress Theme: Translating Discoveries into Prevention and Curesen_US
dc.description.abstractBackground: Lung cancer is the top cancer killer. Squamous cell lung carcinoma (SCC) represents the second most common histologic subtype of lung cancer. Arsenic trioxide (ATO) has been demonstrated to inhibit tumor growth in lung adenocarcinoma and initiate apoptosis in acute promyelocytic leukemia. Fibroblast growth factor (FGF) receptor (FGFR) amplification is shown in some SCC. FGFR inhibitor (e.g. PD173074) has been developed to inhibit FGFR. Methods: The combination effect of ATO and PD173074 was studied using a cell line with FGFR amplification: SK-MES-1. The effect of ATO and/or PD173074 on cell viability and protein expression was studied by MTT assay and Western blot respectively. Cell cycle arrest, phosphatidylserine externalization and mitochondrial membrane depolarization were monitored by flow cytometry. FGFR knockdown was performed with siRNA targeting FGFR. Proteasome inhibitor (MG-132) was used to study the degradation mechanism. The in vivo effect of ATO and/or PD173074 was investigated with a nude mice xenograft model. Results: Combination of ATO and PD173074 reduced cell viability along with increased sub-G1 population, phosphatidylserine externalization and mitochondrial membrane depolarization more significantly than single drug alone. In general, downregulation of FGFR, p-Akt, Akt, p-Src, Src, p-c-Raf, c-Raf, Erk, Bcl-2 and survivin as well as upregulation of p-Erk and cleaved PARP were observed upon ATO and/or PD treatment with or without FGF. MG-132 reversed the degradation of Akt, Src, c-Raf and Erk induced by ATO/PD, but not FGFR, which disclosed proteasome degradation system was involved. Downregulation of FGFR, Akt, Src, c-Raf and Erk as well as cleaved PARP elevation induced by ATO and/or PD were confirmed in vivo. Conclusion: Massive protein degradation (FGFR, Akt, Src, c-Raf and Erk) was induced by ATO and/or PD173074 treatment mainly mediated by activation of proteasome degradation system in SCC cell line SK-MES-1 in vitro and in vivo.en_US
dc.languageengen_US
dc.relation.ispartof21st HKICC 2014en_US
dc.titleCombination effect of arsenic trioxide and FGFR inhibitor through downregulation of FGFR, Akt and Erk in squamous cell lung carcinomaen_US
dc.typeConference_Paperen_US
dc.identifier.emailLam, SK: sklam77@hku.hken_US
dc.identifier.emailHo, JCM: jhocm@hku.hken_US
dc.identifier.authorityHo, JCM=rp00258en_US
dc.identifier.hkuros241619en_US

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