PMID- 26381179
OWN - NLM
STAT- MEDLINE
DCOM- 20160418
LR  - 20211203
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 466
IP  - 3
DP  - 2015 Oct 23
TI  - DNA-PKcs interference sensitizes colorectal cancer cells to a mTOR kinase 
      inhibitor WAY-600.
PG  - 547-53
LID - S0006-291X(15)30585-4 [pii]
LID - 10.1016/j.bbrc.2015.09.068 [doi]
AB  - Colorectal cancer (CRC) is one leading contributor of cancer-related mortalities. 
      Mammalian target of rapamycin (mTOR), existing in two complexes (mTORC1/2), is a 
      valuable target for possible CRC interference. In the current study, we showed 
      that WAY-600, a potent mTOR inhibitor, only exerted moderate activity against 
      primary and HT-29 CRC cells. We proposed that DNA-dependent protein kinase 
      catalytic subunit (DNA-PKcs) could be the major resistance factor of WAY-600 in 
      CRC cells. DNA-PKcs inhibitors, including NU7026 and NU7441, dramatically 
      enhanced WAY-600-induced cytotoxic and pro-apoptotic effect against the CRC 
      cells. Further, WAY-600-exerted cytotoxicity was significantly increased in 
      DNA-PKcs-silenced (by targeted siRNA/shRNA) CRC cells, but was attenuated with 
      DNA-PKcs overexpression. Our evidence suggested that DNA-PKcs Thr-2609 
      phosphorylation might be critical for WAY-600's resistance. Mutation of this site 
      through introducing a dominant negative DNA-PKcs (T2609A) dramatically 
      potentiated WAY-600's sensitivity in HT-29 cells. Meanwhile, overexpression of 
      protein phosphatase 5 (PP5) dephosphorylated DNA-PKcs at Thr-2609, and 
      significantly increased WAY-600's sensitivity in HT-29 cells. In vivo, 
      WAY-600-induced anti-HT-29 xenograft growth activity was significantly 
      potentiated with NU7026 co-administration. These results suggest that DNA-PKcs 
      could be the major resistance factor of WAY-600 in CRC cells.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Wu, Ling
AU  - Wu L
AD  - Gastrointestinal Surgery, Tianjin Baodi Hospital, Tianjin, 301800, China.
FAU - Zhang, Jiansheng
AU  - Zhang J
AD  - Gastrointestinal Surgery, Tianjin Baodi Hospital, Tianjin, 301800, China.
FAU - Wu, Huiguo
AU  - Wu H
AD  - Gastrointestinal Surgery, Tianjin Baodi Hospital, Tianjin, 301800, China.
FAU - Han, Enkun
AU  - Han E
AD  - Gastrointestinal Surgery, Tianjin Baodi Hospital, Tianjin, 301800, China. 
      Electronic address: drhanenjun8@sina.com.
LA  - eng
PT  - Journal Article
DEP - 20150914
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (2-(morpholin-4-yl)benzo(h)chromen-4-one)
RN  - 0 (8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (PRKDC protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Chromones/administration & dosage/pharmacology
MH  - Colorectal Neoplasms/*drug therapy/genetics/*metabolism
MH  - DNA-Activated Protein Kinase/*antagonists & inhibitors/genetics/metabolism
MH  - Drug Resistance, Neoplasm/genetics
MH  - Drug Synergism
MH  - Gene Knockdown Techniques
MH  - HT29 Cells
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Morpholines/administration & dosage/pharmacology
MH  - Nuclear Proteins/*antagonists & inhibitors/genetics/metabolism
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/administration & dosage/pharmacology
MH  - RNA, Small Interfering/genetics
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - Chemo-sensitization
OT  - Colorectal cancer
OT  - DNA-PKcs
OT  - WAY-600
OT  - mTOR
EDAT- 2015/09/19 06:00
MHDA- 2016/04/19 06:00
CRDT- 2015/09/19 06:00
PHST- 2015/09/02 00:00 [received]
PHST- 2015/09/11 00:00 [accepted]
PHST- 2015/09/19 06:00 [entrez]
PHST- 2015/09/19 06:00 [pubmed]
PHST- 2016/04/19 06:00 [medline]
AID - S0006-291X(15)30585-4 [pii]
AID - 10.1016/j.bbrc.2015.09.068 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2015 Oct 23;466(3):547-53. doi: 
      10.1016/j.bbrc.2015.09.068. Epub 2015 Sep 14.