Browsing by Author "Naomoto, Yoshio"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor
    (Elsevier, 2015-07-15) Ishida, Naomasa; Fukazawa, Takuya; Maeda, Yutaka; Yamatsuji, Tomoki; Takaoka, Munenori; Haisa, Minoru; Yokota, Etsuko; Shigemitsu, Kaori; Morita, Ichiro; Kato, Katsuya; Matsumoto, Kenichi; Shimo, Tsuyoshi; Okui, Tatsuo; Bao, Xiao-Hong; Hao, Huifang; Grant, Shawn N.; Takigawa, Nagio; Whitsett, Jeffrey A.; Naomoto, Yoshio; Department of Medicine, Division of Hematology and Oncology, IU School of Medicine
    The PI3K–AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.
  • Thumbnail Image
    Item
    SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma.
    (NPG, 2016) Fukazawa, Takuya; Guo, Minzhe; Ishida, Naomasa; Yamatsuji, Tomoki; Takaoka, Munenori; Yokota, Etsuko; Haisa, Minoru; Miyake, Noriko; Ikeda, Tomoko; Okui, Tatsuo; Takigawa, Nagio; Maeda, Yutaka; Naomoto, Yoshio; Department of Medicine, IU School of Medicine
    Since the SOX2 amplification was identified in lung squamous cell carcinoma (lung SCC), SOX2 transcriptional downstream targets have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including 4 lung SCC cell lines) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A.