PMID- 23950876
OWN - NLM
STAT- MEDLINE
DCOM- 20140306
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 8
DP  - 2013
TI  - Inhibition of both EGFR and IGF1R sensitized prostate cancer cells to radiation 
      by synergistic suppression of DNA homologous recombination repair.
PG  - e68784
LID - 10.1371/journal.pone.0068784 [doi]
LID - e68784
AB  - Reduced sensitivity of prostate cancer (PC) cells to radiation therapy poses a 
      significant challenge in the clinic. Activation of epidermal growth factor 
      receptor (EGFR), type 1 insulin-like growth factor receptor (IGF1R), and 
      crosstalk between these two signaling pathways have been implicated in the 
      development of radiation resistance in PC. This study assessed the effects of 
      targeting both receptors on the regulation of radio-sensitivity in PC cells. 
      Specific inhibitors of EGFR and IGF1R, Erlotinib and AG1024, as well as siRNA 
      targeting EGFR and IGF1R, were used to radio-sensitize PC cells. Our results 
      showed that co-inhibiting both receptors significantly dampened cellular growth 
      and DNA damage repair, and increased radio-sensitivity in PC cells. These effects 
      were carried out through synergistic inhibition of homologous 
      recombination-directed DNA repair (HRR), but not via inhibition of non-homologous 
      end joining (NHEJ). Furthermore, the compromised HRR capacity was caused by 
      reduced phosphorylation of insulin receptor substrate 1 (IRS1) and its subsequent 
      interaction with Rad51. The synergistic effect of the EGFR and IGF1R inhibitors 
      was also confirmed in nude mouse xenograft assay. This is the first study testing 
      co-inhibiting EGFR and IGF1R signaling in the context of radio-sensitivity in PC 
      and it may provide a promising adjuvant therapeutic approach to improve the 
      outcome of PC patients to radiation treatment.
FAU - Wang, Yong
AU  - Wang Y
AD  - Department of Urology, Tangdu Hospital, Fourth Military Medical University, 
      Xi'an, Shaan'xi Province, PR China.
FAU - Yuan, Jian Lin
AU  - Yuan JL
FAU - Zhang, Yun Tao
AU  - Zhang YT
FAU - Ma, Jian Jun
AU  - Ma JJ
FAU - Xu, Peng
AU  - Xu P
FAU - Shi, Chang Hong
AU  - Shi CH
FAU - Zhang, Wei
AU  - Zhang W
FAU - Li, Yu Mei
AU  - Li YM
FAU - Fu, Qiang
AU  - Fu Q
FAU - Zhu, Guang Feng
AU  - Zhu GF
FAU - Xue, Wei
AU  - Xue W
FAU - Lei, Yong Hua
AU  - Lei YH
FAU - Gao, Jing Yu
AU  - Gao JY
FAU - Wang, Juan Ying
AU  - Wang JY
FAU - Shao, Chen
AU  - Shao C
FAU - Yi, Cheng Gang
AU  - Yi CG
FAU - Wang, He
AU  - Wang H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130812
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Tyrphostins)
RN  - 0 (tyrphostin AG 1024)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.7.- (Rad51 Recombinase)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects/genetics/radiation effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - DNA End-Joining Repair
MH  - Disease Models, Animal
MH  - ErbB Receptors/*antagonists & inhibitors/genetics
MH  - Humans
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Male
MH  - Mice
MH  - Prostatic Neoplasms/*genetics/*metabolism/radiotherapy
MH  - Rad51 Recombinase/metabolism
MH  - *Radiation Tolerance/drug effects/genetics
MH  - Radiation-Sensitizing Agents/pharmacology
MH  - Receptor, IGF Type 1/*antagonists & inhibitors/genetics
MH  - *Recombinational DNA Repair/drug effects
MH  - Signal Transduction/drug effects
MH  - Tyrphostins/pharmacology
PMC - PMC3741308
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/08/21 06:00
MHDA- 2014/03/07 06:00
PMCR- 2013/08/12
CRDT- 2013/08/17 06:00
PHST- 2012/12/21 00:00 [received]
PHST- 2013/06/02 00:00 [accepted]
PHST- 2013/08/17 06:00 [entrez]
PHST- 2013/08/21 06:00 [pubmed]
PHST- 2014/03/07 06:00 [medline]
PHST- 2013/08/12 00:00 [pmc-release]
AID - PONE-D-13-01894 [pii]
AID - 10.1371/journal.pone.0068784 [doi]
PST - epublish
SO  - PLoS One. 2013 Aug 12;8(8):e68784. doi: 10.1371/journal.pone.0068784. eCollection 
      2013.