Author of

• 18974

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  P3.02 - Biology/Pathology (ID 620)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 23978

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    P3.02-030 - Inhibitory Effects of Mitochondrial TRAP1 on Gefitinib-Resistance in Non-Small Lung Cancer Cells (ID 8383)

    09:30 - 09:30  |  Presenting Author(s): Euntaik Jeong
    • Abstract

    Background:
    TNF receptor-associated protein 1 (TRAP1) has been reported to be upregulated in some tumors, and protected against apoptosis and oxidative stress. This study was designed to investigate overcoming gefitinib resistance in NSCLC through a mechanism-based approach using gamitrinib variant containing triphenylphosphonium (G-TPP), TRAP1 inhibitor.
    
    Method:
    We developed an in vitro model of acquired resistance to gefitinib by continuously treating HCC827 with escalating doses. The effects of G-TPP on apoptosis and ROS-dependent mitochondrial dysfunction in HCC827GR cells were examined by annexin V binding assay, MitoSoX, and immunoblot analysis. and we tested the effects of pretreated with NAC or DPI, free radical scavenger. In addition, TRAP1 and antioxidant MnSOD were respectively knocked down or overexpressed to determine its role in modulating ROS-mediated apotosis signals by G-TPP.
    
    Result:
    Downregulation of TRAP1 through siRNA or G-TPP enhanced ROS-mediated apoptosis whereas TRAP1 overexpression attenuated ROS-mediated apoptosis induced by gefitinib. On the other hand, pretreatment with NAC or DPI prevents apoptosis induced by gefitinib and G-TPP. We next showed that the combination of gefitinib and G-TPP resulted in decreased expression of MnSOD in HCC827GR cells, not HCC827 cells. MnSOD siRNA and combined with gefitinib and G-TPP resulted in a greater apoptosis. In contrast, overexpression of MnSOD could confer protection against the apoptosis reduced by gefitinib and G-TPP.
    
    Conclusion:
    TRAP1 downregulation could overcome gefitinib resistance in NSCLC via ROS-mediated apoptotic pathway. Moreover, enhanced apoptosis by gefitinib and G-TPP in HCC827GR cells was due, at least in part, to the down-regulation of MnSOD.