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J.C.M. Ho



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    MINI 35 - Biology (ID 161)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI35.04 - Degradation of FGFR1/Akt/Src/C-Raf/Erk by Arsenic Trioxide and FGFR Inhibitor in Squamous Cell Lung Cancer (ID 747)

      18:45 - 18:50  |  Author(s): J.C.M. Ho

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is one of the top cancer killers. Squamous cell lung carcinoma (SCC) represents the second most common histologic subtype of lung cancer. Arsenic trioxide (ATO) inhibits tumor growth and initiates apoptosis in lung adenocarcinoma and acute promyelocytic leukemia. Fibroblast growth factor receptor (FGFR) amplification has been shown in some SCC. FGFR inhibitor (e.g. PD173074) has been developed to inhibit FGFR.

      Methods:
      The combination effect of ATO and PD173074 (PD) was studied using a SCC cell line (SK-MES-1) with FGFR1 amplification. The effect of ATO and/or PD on cell viability and protein expression was studied by MTT assay and Western blot respectively. Cell cycle analysis, phosphatidylserine externalization and mitochondrial membrane depolarization were monitored by flow cytometry. Proteasome inhibitor (MG-132) was used to study the degradation mechanism. The in vivo effect of ATO and/or PD was investigated with a nude mice xenograft model.

      Results:
      Combination of ATO and PD reduced cell viability along with increased sub-G1 population, phosphatidylserine externalization and mitochondrial membrane depolarization, more significantly than single agents alone. Downregulation of FGFR1, p-Akt, Akt, p-Src, Src, p-c-Raf, c-Raf, Erk and survivin as well as upregulation of cleaved PARP were observed upon ATO and/or PD treatment. MG-132 partially reversed the degradation of Akt, Src, c-Raf and Erk induced by ATO/PD, suggesting the involvement of proteasome degradation system (Fig 1). Nonetheless, the mechanism of FGFR1 downregulation remained unknown. Downregulation of FGFR1, Akt, Src, c-Raf and Erk as well as cleaved PARP elevation induced by ATO and/or PD were confirmed in vivo (Fig 2). Figure 1 Figure 2





      Conclusion:
      Massive protein degradation (FGFR1, Akt, Src, c-Raf and Erk) was induced by ATO and/or PD treatment mainly via proteasomal degradation in a SCC cell line (SK-MES-1) in vitro and in vivo. Potential role of combined ATO with FGFR inhibitor in SCC warrants further exploration.

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