PMID- 27294206
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20160613
LR  - 20201001
IS  - 2465-9525 (Print)
IS  - 2465-9541 (Electronic)
IS  - 2465-9525 (Linking)
VI  - 20
IP  - 1
DP  - 2016 Mar
TI  - Blockage of Autophagy Rescues the Dual PI3K/mTOR Inhibitor BEZ235-induced Growth 
      Inhibition of Colorectal Cancer Cells.
PG  - 1-10
LID - 10.12717/DR.2016.20.1.001 [doi]
AB  - Molecular targeting for the altered signaling pathways has been proven to be 
      effective for the treatment ofmany 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 G1 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.
FAU - Oh, Iljoong
AU  - Oh I
AD  - Dept. of Medicine, Jeju National University School of Medicine, Jeju 690-756, 
      Korea.
FAU - Cho, Hyunchul
AU  - Cho H
AD  - Dept. of Medicine, Jeju National University School of Medicine, Jeju 690-756, 
      Korea.
FAU - Lee, Yonghoon
AU  - Lee Y
AD  - Dept. of Medicine, Jeju National University School of Medicine, Jeju 690-756, 
      Korea.
FAU - Cheon, Minseok
AU  - Cheon M
AD  - Dept. of Dermatology, Jeju National University School of Medicine, Jeju 690-756, 
      Korea.
FAU - Park, Deokbae
AU  - Park D
AD  - Dept. of Histology, Jeju National University School of Medicine, Jeju 690-756, 
      Korea.
FAU - Lee, Youngki
AU  - Lee Y
AD  - Dept. of Histology, Jeju National University School of Medicine, Jeju 690-756, 
      Korea.
LA  - eng
PT  - Journal Article
PL  - Korea (South)
TA  - Dev Reprod
JT  - Development & reproduction
JID - 101178352
PMC - PMC4899554
OTO - NOTNLM
OT  - BEZ235
OT  - HCT15 colorectal cancer cell line
OT  - autophagy
OT  - chloroquine
EDAT- 2016/06/14 06:00
MHDA- 2016/06/14 06:01
PMCR- 2016/03/01
CRDT- 2016/06/14 06:00
PHST- 2016/06/14 06:00 [entrez]
PHST- 2016/06/14 06:00 [pubmed]
PHST- 2016/06/14 06:01 [medline]
PHST- 2016/03/01 00:00 [pmc-release]
AID - 10.12717/DR.2016.20.1.001 [doi]
PST - ppublish
SO  - Dev Reprod. 2016 Mar;20(1):1-10. doi: 10.12717/DR.2016.20.1.001.