TY - JOUR
T1 - Development of a Novel Oncolytic Adenovirus Expressing a Short-hairpin RNA against Cullin 4A
AU - Wakabayashi, Keisaku
AU - Sakurai, Fuminori
AU - Ono, Ryosuke
AU - Fujiwara, Toshiyoshi
AU - Mizuguchi, Hiroyuki
PY - 2020
Y1 - 2020
N2 - Background: Arming of an oncolytic adenovirus (OAd) by inserting expression cassettes of therapeutic transgenes into the OAd genome is a promising approach to enhance the therapeutic effects of an OAd. Ideally, this approach would simultaneously promote the replication of an OAd in tumor cells and transgene product-mediated antitumor effects by expressing therapeutic transgenes. We previously demonstrated that knockdown of cullin 4A (CUL4A), which is an E3 ubiquitin ligase, significantly promoted adenovirus replication by increasing the c-JUN protein level. In addition, previous studies reported that CUL4A was highly expressed in various types of tumor, and was involved in tumor growth and metastasis. Materials and Methods: In this study, we developed a novel OAd expressing a short-hairpin RNA (shRNA) against CUL4A (OAdshCUL4A). Results: OAd-shCUL4 mediated higher levels of cytotoxic effects on various types of human tumor cell than a conventional OAd. Higher levels of OAd genome copy numbers were found in the tumor cells for OAd-shCUL4A, compared with a conventional OAd. Conclusion: OAdshCUL4A showed efficient antitumor effects by both enhancing OAd replication and inhibiting tumor cell growth.
AB - Background: Arming of an oncolytic adenovirus (OAd) by inserting expression cassettes of therapeutic transgenes into the OAd genome is a promising approach to enhance the therapeutic effects of an OAd. Ideally, this approach would simultaneously promote the replication of an OAd in tumor cells and transgene product-mediated antitumor effects by expressing therapeutic transgenes. We previously demonstrated that knockdown of cullin 4A (CUL4A), which is an E3 ubiquitin ligase, significantly promoted adenovirus replication by increasing the c-JUN protein level. In addition, previous studies reported that CUL4A was highly expressed in various types of tumor, and was involved in tumor growth and metastasis. Materials and Methods: In this study, we developed a novel OAd expressing a short-hairpin RNA (shRNA) against CUL4A (OAdshCUL4A). Results: OAd-shCUL4 mediated higher levels of cytotoxic effects on various types of human tumor cell than a conventional OAd. Higher levels of OAd genome copy numbers were found in the tumor cells for OAd-shCUL4A, compared with a conventional OAd. Conclusion: OAdshCUL4A showed efficient antitumor effects by both enhancing OAd replication and inhibiting tumor cell growth.
KW - Adenovirus
KW - CUL4A
KW - Oncolytic virus
KW - ShRNA
KW - Virotherapy
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U2 - 10.21873/anticanres.13937
DO - 10.21873/anticanres.13937
M3 - Article
C2 - 31892564
AN - SCOPUS:85077457701
VL - 40
SP - 161
EP - 168
JO - Anticancer Research
JF - Anticancer Research
SN - 0250-7005
IS - 1
ER -