PMID- 25152407
OWN - NLM
STAT- MEDLINE
DCOM- 20141124
LR  - 20221207
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 452
IP  - 1
DP  - 2014 Sep 12
TI  - DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 
      pancreatic cancer cells.
PG  - 106-11
LID - S0006-291X(14)01482-X [pii]
LID - 10.1016/j.bbrc.2014.08.059 [doi]
AB  - 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.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Hu, Hao
AU  - Hu H
AD  - The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, 
      Wuxi City, Jiangsu Province 214000, China. Electronic address: 
      haoge123478@163.com.
FAU - Gu, Yuanlong
AU  - Gu Y
AD  - The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, 
      Wuxi City, Jiangsu Province 214000, China.
FAU - Qian, Yi
AU  - Qian Y
AD  - The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, 
      Wuxi City, Jiangsu Province 214000, China.
FAU - Hu, Benshun
AU  - Hu B
AD  - The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, 
      Wuxi City, Jiangsu Province 214000, China.
FAU - Zhu, Congyuan
AU  - Zhu C
AD  - The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, 
      Wuxi City, Jiangsu Province 214000, China.
FAU - Wang, Gaohe
AU  - Wang G
AD  - The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, 
      Wuxi City, Jiangsu Province 214000, China.
FAU - Li, Jianping
AU  - Li J
AD  - The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, 
      Wuxi City, Jiangsu Province 214000, China. Electronic address: 
      jianpingwuxi1974@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140821
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0W860991D6 (Deoxycytidine)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Cell Line, Tumor
MH  - DNA-Activated Protein Kinase/*metabolism
MH  - Deoxycytidine/*analogs & derivatives/pharmacology
MH  - Enzyme Activation
MH  - Humans
MH  - Pancreatic Neoplasms/enzymology/*pathology
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Gemcitabine
OTO - NOTNLM
OT  - Akt and chemo-resistance
OT  - DNA-PKcs
OT  - Gemcitabine
OT  - Pancreatic cancer
EDAT- 2014/08/26 06:00
MHDA- 2014/12/15 06:00
CRDT- 2014/08/26 06:00
PHST- 2014/08/08 00:00 [received]
PHST- 2014/08/13 00:00 [accepted]
PHST- 2014/08/26 06:00 [entrez]
PHST- 2014/08/26 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
AID - S0006-291X(14)01482-X [pii]
AID - 10.1016/j.bbrc.2014.08.059 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2014 Sep 12;452(1):106-11. doi: 
      10.1016/j.bbrc.2014.08.059. Epub 2014 Aug 21.