Author of

• 14490

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  P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

  • Event: WCLC 2015
  • Type: Poster
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)

  • 14535

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    P2.04-045 - Targeting eIF4A1 and eIF4A2 mRNA Helicases in Pulmonary Adenocarcinoma (ID 2703)

    09:30 - 09:30  |  Author(s): J. Le Quesne
    • Abstract

    Background:
    Neoplasia is frequently associated with dysregulated mRNA translation. This dysregulation facilitates tumour growth by promoting proliferation, survival and angiogenesis. Translation is mostly regulated at the initiation stage during which translation initiation factors facilitate positioning of the translation-competent ribosome at the start codon of mRNA. Eukaryotic initiation factors 4A1 and 4A2 are ATP-dependent DEAD-box helicases that unwind 5’ UTR as a subunit of the eIF4F complex. eIF4A2 shares 91% amino-acid sequence identity with eIF4A1 and has been implicated in mRNA-mediated silencing. Studies have suggested separate roles for the two eIF4A isoforms. High-level expression of eIF4A1 in early stage non-small cell lung cancer (NSCLC) primary tumours was shown to be associated with poor survival, and, recently, downregulation of eIF4A2 was shown to promote NSCLC progression. Small molecule inhibitors of eIF4A have been shown to have anticancer effects in cell culture and xenograft models. Thus, eIF4A1 and eIf4A2 hold promise as important mediators in lung cancer. This study aims to elucidate the role of eIF4A1 and eIF4A2 in the development of malignant phenotype in pulmonary adenocarcinoma.
    
    Methods:
    This study employed two human cancer cell lines as a model for pulmonary adenocarcinoma: HCC364 and H2228. eIF4A activity was modified by using hippuristanol, a non-specific allosteric small molecule inhibitor of both eIF4A isoforms, and siRNA-mediated knockdown of eIFA1 or eIF4A2. Cell cycle analysis was performed using EdU labelling and flow cytometry and cell proliferation was measured by cell counting, xCELLigence and WST metabolic assays. Effects of eIf4A inhibition on protein translation were studied through polysome profiling.
    
    Results:
    Both adenocarcinoma cell lines showed significant reduction in S-phase cell population and metabolic activity when treated with hippuristanol. Polysome profiling of HCC364 cells treated with hippuristanol revealed a substantial decrease in polysomal fractions accompanied with the liberation of ribosomal units. Although siRNA-mediated silencing of eIF4A1 markedly suppressed cell proliferation in HCC364 cells, the H2228 cells were unaffected. Interestingly, silencing of eIF4A2 in H2228 cells sometimes results in marked hyperproliferation.
    
    Conclusion:
    Our data suggest very different roles of eIF4A isoforms in lung cancer, which have major implications for possible anti-eIF4A therapies. In particular, it suggests that inhibition of eIF4A2 may have a growth-promoting effect in some tumours. As current small molecule inhibitors are non-specific between the two isoforms, this has major implications for the use of similar compounds in a clinical setting.