Author of

• 11454

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  P2.01 - Poster Session 2 - Cancer Biology (ID 145)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11477

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    P2.01-023 - ER homeostasis and motility of NSCLC cell lines can be therapeutically targeted with combined Hsp90 and HDAC inhibitors. (ID 1042)

    09:30 - 09:30  |  Author(s): L. Drucker
    • Abstract

    Background
    Lung cancer remains the most common cause of cancer-related death in the world for which novel systemic treatments are urgently needed. Protein homeostasis that regulates protein levels and their fold is critical for cancer cell proliferation and survival. A complex network of cellular organelles and signaling cascades is involved in control of protein homeostasis including endoplasmatic reticulum (ER). Thus, proteins in control of ER homeostasis are increasingly recognized as potential therapeutic targets. Molecular chaperone heat shock protein 90 (Hsp90) and histone deacetylase (HDAC) play an important role in ER homeostasis. Previous studies demonstrate that Hsp90 and HDAC inhibitors are individually functional against lung cancer. In this work we suggested that combined Hsp90 and HDAC inhibitors may elevate ER stress thereby enhancing the anti non small lung cancer (NSCLC) activity.

    Methods
    NSCLC cell lines (A549, H1299, H460) were treated with 17-DMAG (Hsp90 inhibitor), PTACH (HDAC inhibitor) and both drugs simultaneously for 24 hours. Cells were harvested and analyzed for ER stress markers (Immunoblot), viability (WST1 assay), motility (Scratch assay), and death (Flow cytometer).

    Results
    Using an in vitro cell line model we demonstrated that 17-DMAG co-administration with PTACH caused elevated ER stress (more than 110%, p<0.05) accompanied by apoptotic cell death (Annexin V) (7-21%, p<0.05). Moreover, 17-DMAG/PTACH treated cells lost the ability to migrate (57-85% of scratch closure, p<0.05).

    Conclusion
    Our findings provide proof-of-concept that targeting ER homeostasis is therapeutically beneficial in lung cancer cell lines. Indeed, the elevated ER stress caused by 17-DMAG/PTACH combined treatment leads to increased cell death of NSCLC cell lines compared to the application of the drugs separately.

• 12364

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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

  • 12384

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    P3.01-020 - Bone marrow mesenchymal stem cells deleteriously affect lung cancer cell lines. (ID 1034)

    09:30 - 09:30  |  Author(s): L. Drucker
    • Abstract

    Background
    Lung cancer remains the most common cause of cancer-related death in the world. The major advances in treatment of lung cancer have brought only minor improvements in survival; therefore novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Therefore, we decided to study the effect of bone marrow (BM) MSCs on non small cell lung cancer (NSCLC) cell lines. Recent studies indicate that translation initiation factors are over expressed in multiple cancers and negatively impact NSCLC prognosis. Interestingly, translation initiation is highly modulated by microenvironmental cues. Hence, special emphasis will be attributed to the role of translation initiation in the crosstalk between the malignant lung cells and the BM-MSCs.

    Methods
    Specifically, we will determine the influence of MSCs (co-culture) and MSCs conditioned media on the proliferation, viability, migration of NSCLC cell lines (A549, H1299, and H460). We will also explore the effect on translation initiation factors implicated in cancer progression (eIF4E, eIF4GI, DHX29).

    Results
    Preliminary results demonstrate that 48h co-culture of NSCLC cell lines with MSCs conditioned media significantly decreased cell number (A549: 60%, H1299: 50%, H460: 10%, p<0.05) and viability (A549: 70%, H1299: 50%, H460: 60%, p<0.01) yet had no effect on cell cycle or death. Moreover, MSCs conditioned media decreased NSCLC cells motility (H1299: 60%, H460: 70%, p<0.05) and attenuated eIF4GI expression and activity as indicated by the levels of its targets (H1299: peIF4G 65%, total eIF4G 40%, SMAD5 30%, cMyc 80%; H460: peIF4G 90%, SMAD5 85%, cMyc 40%, p<0.05).

    Conclusion
    Ongoing work in our lab is aimed at dissecting whether the effects are dependent on direct cell-cell contact or mediated by soluble factors. Results that indicate translation initiation is modulated by MSCs derived components will mark new therapeutic targets for lung cancer treatment.