skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells

Abstract

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.

Authors:
; ;
Publication Date:
OSTI Identifier:
22719060
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 490; Journal 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); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CELL PROLIFERATION; DNA; FEEDBACK; INHIBITION; LARGE INTESTINE; NEOPLASMS; PROTEINS

Citation Formats

Mao, Mintao, Liu, Yumei, and Gao, Xinhai. Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2017.07.002.
Mao, Mintao, Liu, Yumei, & Gao, Xinhai. Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells. United States. doi:10.1016/J.BBRC.2017.07.002.
Mao, Mintao, Liu, Yumei, and Gao, Xinhai. Sat . "Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells". United States. doi:10.1016/J.BBRC.2017.07.002.
@article{osti_22719060,
title = {Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells},
author = {Mao, Mintao and Liu, Yumei and Gao, Xinhai},
abstractNote = {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.},
doi = {10.1016/J.BBRC.2017.07.002},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 4,
volume = 490,
place = {United States},
year = {2017},
month = {9}
}