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Identification of FES as a Novel Radiosensitizing Target in Human Cancers

Authors
 Byoung Hyuck Kim  ;  Yong Joon Kim  ;  Myung-Ho Kim  ;  Yi Rang Na  ;  Daun Jung  ;  Seung Hyeok Seok  ;  Joon Kim  ;  Hak Jae Kim 
Citation
 CLINICAL CANCER RESEARCH, Vol.26(1) : 265-273, 2020-01 
Journal Title
 CLINICAL CANCER RESEARCH 
ISSN
 1078-0432 
Issue Date
2020-01
Abstract
Purpose: The identification of novel targets for developing synergistic drug-radiation combinations would pave the way to overcome tumor radioresistance. We conducted cell-based screening of a human kinome siRNA library to identify a radiation-specific kinase that has a synergistic toxic effect with radiation upon inhibition and is not essential for cell survival in the absence of radiation. Experimental design: Unbiased RNAi screening was performed by transfecting A549 cells with a human kinome siRNA library followed by irradiation. Radiosensitizing effects of a target gene and involved mechanisms were examined. Results: We identified the nonreceptor protein tyrosine kinase FES (FEline Sarcoma oncogene) as a radiosensitizing target. The expression of FES was increased in response to irradiation. Cell viability and clonogenic survival after irradiation were significantly decreased by FES knockdown in lung and pancreatic cancer cell lines. In contrast, FES depletion alone did not significantly affect cell proliferation without irradiation. An inducible RNAi mouse xenograft model verified in vivo radiosensitizing effects. FES-depleted cells showed increased apoptosis, DNA damage, G2-M phase arrest, and mitotic catastrophe after irradiation. FES depletion promoted radiation-induced reactive oxygen species formation, which resulted in phosphorylation of S6K and MDM2. The radiosensitizing effect of FES knockdown was partially reversed by inhibition of S6K activity. Consistent with the increase in phosphorylated MDM2, an increase in nuclear p53 levels was observed, which appears to contribute increased radiosensitivity of FES-depleted cells. Conclusions: We uncovered that inhibition of FES could be a potential strategy for inducing radiosensitization in cancer. Our results provide the basis for developing novel radiosensitizers.
Full Text
https://clincancerres.aacrjournals.org/content/26/1/265.long
DOI
10.1158/1078-0432.CCR-19-0610
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Yong Joon(김용준)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/176022
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