한국발생생물학회지:발생과생식 (Development and Reproduction)

  • 제20권1호
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  • Pages.1-10
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  • 2016
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  • 2465-9525(pISSN)
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  • 2465-9541(eISSN)
한국발생생물학회 (The Korean Society of Developmental Biology)
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Blockage of Autophagy Rescues the Dual PI3K/mTOR Inhibitor BEZ235-induced Growth Inhibition of Colorectal Cancer Cells

  • Oh, Iljoong (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Cho, Hyunchul (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Lee, Yonghoon (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Cheon, Minseok (Dept. of Dermatology, Jeju National University School of Medicine) ;
  • Park, Deokbae (Dept. of Histology, Jeju National University School of Medicine) ;
  • Lee, Youngki (Dept. of Histology, Jeju National University School of Medicine)
  • 투고 : 2015.12.22
  • 심사 : 2016.01.08
  • 발행 : 2016.03.31
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초록

Molecular targeting for the altered signaling pathways has been proven to be effective for the treatment of many types of human cancer, including colorectal cancer (CRC). The dual phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 has shown to exhibit potent antitumor activity against solid tumors. Autophagy is a cellular lysosomal catabolic process to maintain metabolic homeostasis, which has been known to be induced in response to many therapeutic agents in cancer cells. This process is negatively regulated by mTOR and often acts as prosurvival or prodeath mechanism following cancer therapeutics. The current study was designed to investigate the antiproliferation activity of BEZ235 and to evaluate the role of autophagy induced by BEZ235 using HCT15 CRC cells bearing ras oncogene mutation. We found that BEZ235 decreases cell viability, which was mostly dependent on $G_1$ arrest of cell cycle via suppression of cyclin A expression. BEZ235 affects PI3K/Akt/mTOR signaling pathway by increasing the phosphorylation of AKT at $Ser^{473}$ and RAS/RAF/MEK/ERK pathway by decreasing the phosphorylation of ERK at $Tyr^{204}$. BEZ235 also stimulated autophagy induction as evidenced by the increased expression of LC3-II and abundant acidic vesicular organelles (AVOs) in the cytoplasm. In addition, the combination of BEZ235 with autophagy inhibitor chloroquine, a known antagonist of autophagy, counteracted the antiproliferation effect of BEZ235. Thus, our study indicates that autophagy induced in response to BEZ235 treatment appears to act as cell death mechanism in HCT15 CRC cells.

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