Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells
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, Vol. 490, Issue 4; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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