Author of

• 18272

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  P3.01 - Poster Session with Presenters Present (ID 469)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 18306

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    P3.01-034 - Migration and Epithelial to Mesenchymal Transition of Lung Cancer Can Be Targeted via Translation Initiation Factors eIF4E and eIF4GI (ID 3685)

    14:30 - 14:30  |  Author(s): L. Drucker
    • Abstract

    Background:
    Background: Non small cell lung cancer (NSCLC) metastasis remains a major cause for patient mortality marking the underlying molecular mechanisms as important therapeutic targets. The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority NSCLC patients deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Deregulation of protein synthesis is integral to the malignant phenotype and translational control is emerging as an important factor in tumorigenesis. Indeed, over-expression of translation initiation factors eIF4E and eIF4GI in NSCLC was associated with patients' poor survival. Thus, in this study we aimed to assess the direct role of eIF4E and eIF4GI in NSCLC and their effect on migration and metastasis formation.
    
    Methods:
    Methods: eIF4E/ eIF4GI knockdown (KD) in NSCLC cell lines (H1299, H460) was achieved by siRNA. Following transfection the cells were tested for changes in eIF4E/eIF4GIs' targets (SMAD5, NFkB, cMYC, HIF1α), migration (scratch) and pro/ anti Epithelial-Mesenchymal Transition (EMT) markers (N-Cadherin, Slug, ZEB1, E-Cadherin, Claudin, ZO-1, microRNA). Importance of eIF4E and eIF4GI KD to NSCLC phenotype was further corroborated with the inhibitors ribavirin and 4EGI-1. Lastly, we tested for changes in essential microRNA implicated in NSCLC cell migration and EMT.
    
    Results:
    Results: Downregulation of eIF4E/eIF4GI significantly decreased their established targets (20-35%↓, 48h, p<0.05) indicating compromised activity. Diminished NSCLC cell lines' migration upon eIF4E/eIF4GI KD was also witnessed (65-82%↓, 48h, p<0.05). Moreover, we demonstrated reduced levels of EMT inducers together with elevated levels of EMT suppressors (40-90%↓, 48h, p<0.05). Finally, we showed that eIF4E/eIF4GI KD affected microRNAs critically involved in migration and EMT processes.
    
    Conclusion:
    Conclusions: Our study shows that targeting eIF4E/eIF4GI reduces migration and EMT, both essential for metastasis, thereby underscoring the role of translation initiation in NSCLC metastatic tumor formation. Understanding the molecular events which promote metastasis and improving the means of foretelling their development is a major goal of current clinical research. We suggest that targeting translation initiation in NSCLC with clinically employed drugs that inhibit eIF4E/eIF4GI (Ribavirin/ 4EGI) may afford a valid and effective therapeutic strategy in NSCLC patients and may diminish lung cancer metastatic spread and morbidity and improve the patient's life quality.