Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells
Journal Article
·
· Biochemical and Biophysical Research Communications
The current study evaluated the potential anti-colorectal cancer (CRC) activity by Ku-0060648, a novel DNA-PKcs and PI3K duel inhibitor. In both CRC cell lines (HCT-116 and HT-29) and primary human colon cancer cells, Ku-0060648 exposure at nM concentrations efficiently inhibited cell proliferation. Meanwhile, Ku-0060648 provoked apoptosis in CRC cells. Ku-0060648 was yet ineffective to the normal colon epithelial cells. Ku-0060648 blocked PI3K-AKT-mTOR cascade and in-activated DNA-PKcs in CRC cells. Intriguingly, Ku-0060648 treatment induced feedback autophagy activation in HCT-116 cells. On the other hand, pharmacological autophagy inhibitors (3-methyladenine or chloroquine) or silencing key autophagy proteins (Beclin-1 or ATG-7) dramatically potentiated Ku-0060648-induced HCT-116 cell apoptosis. Together, these results suggest that feedback autophagy activation is a key resistance factor of Ku-0060648 in CRC cells, and autophagy inhibition sensitizes Ku-0060648-induced anti-CRC activity. - Highlights: • Ku-0060648 inhibits colorectal cancer (CRC) cell proliferation. • Ku-0060648 provokes apoptosis in CRC cells. • Ku-0060648 concurrently in-activates AKT-mTOR and DNA-PK in CRC cells. • Ku-0060648 induces feedback autophagy activation in CRC cells. • Autophagy inhibition sensitizes Ku-0060648-meidated anti-CRC cell activity.
- OSTI ID:
- 22719060
- Journal Information:
- Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 490; ISSN 0006-291X; ISSN BBRCA9
- Country of Publication:
- United States
- Language:
- English
Similar Records
Autophagy prevention sensitizes AKTi-1/2-induced anti-hepatocellular carcinoma cell activity in vitro and in vivo
GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth
Gab3 is required for human colorectal cancer cell proliferation
Journal Article
·
Thu Nov 17 23:00:00 EST 2016
· Biochemical and Biophysical Research Communications
·
OSTI ID:22696692
GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth
Journal Article
·
Sat Sep 15 00:00:00 EDT 2018
· Biochemical and Biophysical Research Communications
·
OSTI ID:23105536
Gab3 is required for human colorectal cancer cell proliferation
Journal Article
·
Sat Mar 18 00:00:00 EDT 2017
· Biochemical and Biophysical Research Communications
·
OSTI ID:22696908