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L. Moro



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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.02-013 - SDHB is overexpressed and may be a candidate target for therapeutic intervention in Malignant Pleural Mesothelioma (ID 3287)

      09:30 - 09:30  |  Author(s): L. Moro

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. The Succinate Dehydrogenase Complex, Subunit B, IronSulfur Protein (SDHB), is a subunit of the Succinate dehydrogenase or succinate-coenzyme Q reductase (SQR) or respiratory Complex II, and has recently been identified by us as an important element in MPM.

      Methods
      A panel of MPM cell lines inluding the normal pleural cells LP9 & Met5A were screened for expression of SDHB by RT-PCR. Levels were subsequently examined in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic, and sarcomatoid histologies by RT-PCR and western blot. Finally the expression of SDHB in a large cohort of MPM specimens with clinical data was asessed by IHC.

      Results
      Expression of SDHB occurs in all cell lines. Significantly higher expression of SDHB is observed in the malignant tumour material versus benign pleura. There was a trend towards better survival for patients expressing higher levels of SDHB, but this was not statistically significant.

      Conclusion
      SDHB, a key member of oxidative energy metabolism is significantly altered in MPM. This may have important future implications for the management of MPM.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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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): L. Moro

      • 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.