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  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

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    P3.01-014 - Expression and post-translational modifications of AKT isoforms in Malignant pleural Mesothelioma cells (ID 3252)

    09:30 - 09:30  |  Author(s): E. Borroni
    • Abstract

    Background
    Background: The PI3K/AKT signaling pathway is aberrantly active and has an important biologic impact in malignant pleural mesothelioma (MMe) cell cycle progression and chemo-resistance. Akt consists of three isoforms, Akt1, Akt2, and Akt3. Despite the growing amount of research demonstrating the existence of isoform-specific regulation, many papers still draw generalized conclusions about AKT without focusing on functional specificity of each isoforms. Recent data have clearly demonstrated a role of SIRT1 in the modulation of AKT1 activation and a role of PARP1 as a gatekeeper for SIRT1 activity by limiting NAD+ availability.

    Methods
    Methods: We explored the expression of AKT isoforms in MMe in vivo and in vitro and the balancing between their acetylation and phosphorylation status in human MMe derived cell lines in vitro.

    Results
    Results: We firstly described that MMe tumors in vivo and MMe derived cell lines express both AKT1 and AKT3 isoforms but not AKT2, and their expression results significantly increased in the biphasic histotype. Furthermore, we demonstrated an inverse correlation between AKTs acetylation and phosphorylation modulated by PARP1/SIRT1 activation status. By immunoprecipitation experiments, we evidenced that in basal conditions AKT1 is in part acetylated and in part phosphorylated and became highly phosphorylated and completely de-acetylated upon PARP1 inhibition. Interestingly, AKT1 activation, related to PARP1 inhibition, is unable to modulate pro-survival signals, because the downstream pathway is interrupted at the level of its effector mTOR. Conversely, SIRT1 inhibition or silencing result in a more evident AKT1 and its interactors acetylation.

    Conclusion
    Conclusions: In conclusion, our results clearly show how both PARP1 and SIRT1 affect critical cellular pathways involved in MMe progression and offer a model of a regulatory inter-relationship between these proteins. These data could be helpful for designing new effective therapeutic strategies.