Inhibition of both EGFR and IGF1R sensitized prostate cancer cells to radiation by synergistic suppression of DNA homologous recombination repair.
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.
Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaan'xi Province, PR China.
Yong
Y
Wang
Jian Lin
JL
Yuan
Yun Tao
YT
Zhang
Jian Jun
JJ
Ma
Peng
P
Xu
Chang Hong
CH
Shi
Wei
W
Zhang
Yu Mei
YM
Li
Qiang
Q
Fu
Guang Feng
GF
Zhu
Wei
W
Xue
Yong Hua
YH
Lei
Jing Yu
JY
Gao
Juan Ying
JY
Wang
Chen
C
Shao
Cheng Gang
CG
Yi
He
H
Wang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D059766:DNA End-Joining Repair; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000532:radiotherapy; D051135:Rad51 Recombinase / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D059767:Recombinational DNA Repair / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D055504:Insulin Receptor Substrate Proteins; D011838:Radiation-Sensitizing Agents; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D051135:Rad51 Recombinase