DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells.

Abstract

Pancreatic cancer is one of the most aggressive human malignancies with extremely poor prognosis. The moderate activity of the current standard gemcitabine and gemcitabine-based regimens was due to pre-existing or acquired chemo-resistance of pancreatic cancer cells. In this study, we explored the potential role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in gemcitabine resistance, and studied the underlying mechanisms. We found that NU-7026 and NU-7441, two DNA-PKcs inhibitors, enhanced gemcitabine-induced cytotoxicity and apoptosis in PANC-1 pancreatic cancer cells. Meanwhile, PANC-1 cells with siRNA-knockdown of DNA-PKcs were more sensitive to gemcitabine than control PANC-1 cells. Through the co-immunoprecipitation (Co-IP) assay, we found that DNA-PKcs formed a complex with SIN1, the latter is an indispensable component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). DNA-PKcs-SIN1 complexation was required for Akt activation in PANC-1 cells, while inhibition of this complex by siRNA knockdown of DNA-PKcs/SIN1, or by DNA-PKcs inhibitors, prevented Akt phosphorylation in PANC-1 cells. Further, SIN1 siRNA-knockdown also facilitated gemcitabine-induced apoptosis in PANC-1 cells. Finally, DNA-PKcs and p-Akt expression was significantly higher in human pancreatic cancer tissues than surrounding normal tissues. Together, these results show that DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells.

• Authors: Hao Hu, Yuanlong Gu, Yi Qian, Benshun Hu, Congyuan Zhu, Gaohe Wang, Jianping Li
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 452 Issue 1 Pg. 106-11 (Sep 12 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 25152407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Antimetabolites, Antineoplastic
• Deoxycytidine
• DNA-Activated Protein Kinase
• Proto-Oncogene Proteins c-akt
• Gemcitabine

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• DNA-Activated Protein Kinase (metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Enzyme Activation
• Humans
• Pancreatic Neoplasms (enzymology, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Gemcitabine