Blockage of Autophagy Rescues the Dual PI3K/mTOR Inhibitor BEZ235-induced Growth Inhibition of Colorectal Cancer Cells.
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.
Dept. of Medicine, Jeju National University School of Medicine, Jeju 690-756, Korea.
Iljoong
I
Oh
Dept. of Medicine, Jeju National University School of Medicine, Jeju 690-756, Korea.
Hyunchul
H
Cho
Dept. of Medicine, Jeju National University School of Medicine, Jeju 690-756, Korea.
Yonghoon
Y
Lee
Dept. of Dermatology, Jeju National University School of Medicine, Jeju 690-756, Korea.
Minseok
M
Cheon
Dept. of Histology, Jeju National University School of Medicine, Jeju 690-756, Korea.
Deokbae
D
Park
Dept. of Histology, Jeju National University School of Medicine, Jeju 690-756, Korea.
Youngki
Y
Lee
BEZ235; HCT15 colorectal cancer cell line; autophagy; chloroquine