Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery.
The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer.
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, Japan.
Shinji
S
Kuroda
Toshiya
T
Fujiwara
Yasuhiro
Y
Shirakawa
Yasumoto
Y
Yamasaki
Shuya
S
Yano
Futoshi
F
Uno
Hiroshi
H
Tazawa
Yuuri
Y
Hashimoto
Yuichi
Y
Watanabe
Kazuhiro
K
Noma
Yasuo
Y
Urata
Shunsuke
S
Kagawa
Toshiyoshi
T
Fujiwara
D017766:Acid Anhydride Hydrolases; D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D017501:Adenovirus E1B Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects*; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics / Q000628:therapy; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009687:Nuclear Proteins / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D011839:Radiation, Ionizing; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D017501:Adenovirus E1B Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D019098:Telomerase; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes