Author of

• 12364

  +

  P3.01 - Poster Session 3 - Cancer Biology (ID 147)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12373

    +

    P3.01-009 - FGF-2 induces chemoresistance in model and lung cancer cells through S6K2/hnRNPA1-mediated enhanced translation of anti-apoptotic proteins (ID 2252)

    09:30 - 09:30  |  Author(s): O. Pardo
    • Abstract

    Background
    Most patients die from lung cancer because of chemoresistant metastatic disease. We have previously identified the importance of fibroblast growth factor 2 (FGF2) /S6 kinase 2 (S6K2) signalling in mediating multidrug resistance in lung cancer through enhanced translation of antiapoptotic proteins, such as BCL-XL and XIAP. Here we investigate the downstream mediator(s) of this translational response and demonstrate its relevance in a lung cancer tissue array.

    Methods
    We used tandem affinity purification using S6K2 as bait as well as quantitative phospho-proteomics in the presence and absence of FGF2 stimulation in small cell lung cancer and HEK 293 cells to identify new S6K2 interactors and downstream mediators of the FGF2 pathway. Interactors were validated by co-immunopreciptation experiments and their functional significance examined by siRNA and expression of wild-type or phosphomutant forms. The clinical significance of our in vitro findings were examined in lung cancer tissue arrays.

    Results
    Here, we show that S6K2 interacts with and phosphorylates the heteronuclear ribonuclear protein hnRNPA1 on Ser 4 and 6. This increases the association of this protein with BCL-XL and XIAP mRNAs to promote their nuclear export while de-repressing their translation. A non-phosphorylatible S4/6A hnRNPA1 mutant prevented this process from occurring and impaired the pro-survival activity of FGF2/S6K2 signalling. Following phosphorylation and transfer to the cytoplasm in complex with mRNAs, phospho-hnRNPA1 associates with 14-3-3 to be sumoylated on K189 within a multi-protein complex involving UBC9. This targets hnRNPA1 for re-import into the nucleus in a caryopherin-dependent manner, a step that is essential for translational derepression of target mRNAs. Our in vitro findings predicted that in cancer cells where FGF2/S6K2 signalling is switched on, hnRNPA1 would be predominantly localised to the nucleus and cytoplasmic expression of anti-apoptotic proteins such as BCL-XL would be increased. To test this hypothesis, we stained a NSCLC tissue array for S6K2, hnRNPA1 and BCL-XL expression. Strikingly, this revealed that increased S6K2 expression tightly correlated with decreased cytoplasmic hnRNPA1 and increased BCL-XL levels.

    Conclusion
    FGF-2/S6K2 signalling promotes the nucleo-cytoplasmic cycling of hnRNPA1 to promote tumour cell survival through increased translation of the anti-apoptotic proteins BCL-XL and XIAP. Our immunohistochemical findings in NSCLC suggests that tumours which show absence of cytoplasmic hnRNPA1 in the presence of increased S6K2 and Bcl-XL expression might respond better to FGF receptor inhibitors.