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  • Küçük Resim
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    Dual suppressive effect of miR-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasion
    (Amer Assoc Cancer Research, 2018) Bayraktar, Recep; Ivan, Cristina; Bayraktar, Emine; Kanlıkılıçer, Pınar; Kabil, Nashwa N.; Kahraman, Nermin; Mokhlis, Hamada A.; Karakaş Zeybek, Didem; Rodriguez-Aguayo, Cristian; Arslan, Ahmet; Sheng, Jianting; Wong, Stephen; Lopez-Berestein, Gabriel; Calin, George A.; Özpolat, Bülent
    Purpose: Recent studies indicated that dysregulation of noncoding KNAs (ncRNA) such as miRNAs is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC). Experimental Design: We performed in vitro functional assays on TNBC cell lines to investigate the role of mi R-34a in FOLM1/eEF2K signaling axis. TNBC tumor xenograft models were used for in vivo therapeutic delivery of miR-34a. Results: In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic eEF2K, which was associated with significantly shorter overall patient survival, We showed that miR-34a directly binds to the 3'-untranslated region of eEF2K and FOXM1 mRNAs and suppresses their expression, leading to inhibition of TNBC cell proliferation, motility, and invasion. Notably, restoring miR-34a expression recapitulated the effects of inhibition of eEF2K and FOXM1, the transcription factor for eEF2K and the direct target of p53, in TNBC cell lines, whereas overexpression of eEF2K and FOXM1 rescued the effects and signaling pathways mediated by miR-34a. Moreover, in vivo therapeutic delivery of miR-34a nanopartides by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis, and inducing apoptosis. Conclusions: Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a-based gene therapy may be a potential therapeutic strategy in TNBC. (C)2018 AACR.
  • Küçük Resim
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    Identification of microenvironmental regulation and therapeutic targeting of oncogenic eEF2K in pancreatic cancer
    (Wiley, 2019) Karakaş Zeybek, Didem; Kahraman, Nermin; Bayraktar, Recep; Kabil, Nashwa; Ulukaya, Engin; Dere, Egemen; Berestein, Gabriel Lopez; Özpolat, Bülent
    Eukaryotic elongation factor 2 kinase (eEF2K) is overexpressed in cancer cells and its overexpression is correlated with poor prognosis in several types of cancer. It has been known that pancreatic cancer (PaCa) has a unique tumor microenvironment (TME) which contributes all stages of tumorigenesis. In this study, the effects of interaction between PaCa cells and macrophages on eEF2K levels and aggressive tumor behaviours were investigated.
  • Küçük Resim
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    Identification of microenvironmental regulation and therapeutic targeting of ongenic EF-2 kinase in pancreatic cancer
    (Science Direct, 2018) Karakaş Zeybek, Didem; Kahraman, Nermin; Bayraktar, Recep; Kabil, Nashwa; Ulukaya, Engin; Dere, Egemen; Lopez-Berestein, Gabriel; Özpolat, Bülent
    Introduction Pancreatic cancer (PaCa) is one of the most aggressive and deadliest cancer with 6 months average survival rate. Recent studies indicate that the tumour microenvironment (TME) plays an important role in all stages of tumorigenesis in PaCa. Therefore, both tumour cells and their TME should be targeted for an effective treatment. Eukaryotic elongation factor 2 kinase (EF2K) is an enzyme which is overexpressed in cancer cells and plays a key role in cancer cell survival under stress conditions. There is no study that have shown the relationship between EF2K and TME. Thus, we investigated that the effects of EF2K expression on PaCa cell line (PANC1) and the TME.