An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

被引：6

作者：

Thao Thi Thanh Nguyen ^{[1
,2
,3
]}

Shingyoji, Masato ^{[4
]}

Hanazono, Michiko ^{[1
,5
]}

Zhong, Boya ^{[1
,2
]}

Morinaga, Takao ^{[1
]}

Tada, Yuji ^{[6
,7
]}

Shimada, Hideaki ^{[8
]}

Hiroshima, Kenzo ^{[5
,9
]}

Tagawa, Masatoshi ^{[1
,5
,10
]}

机构：

[1] Chiba Canc Ctr Res Inst, Div Pathol & Cell Therapy, Chuo Ku, 666-2 Nitona, Chiba 2608717, Japan

[2] Chiba Univ, Grad Sch Med, Dept Mol Biol & Oncol, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan

[3] Biotechnol Ctr Ho Chi Minh City, Div Med Biotechnol, 2374 Natl Highway 1,Dist 12, Ho Chi Minh, Vietnam

[4] Chiba Canc Ctr, Div Respirol, Chuo Ku, 666-2 Nitona, Chiba 2608717, Japan

[5] Chiba Univ, Grad Sch Med, Dept Biochem & Genet, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan

[6] Chiba Univ, Grad Sch Med, Dept Respirol, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan

[7] Int Univ Hlth & Welf Atami Hosp, Dept Resp Med, 13-1 Higasikaigan, Atami 4130012, Japan

[8] Toho Univ, Grad Sch Med, Dept Surg, Oota Ku, 6-11-1 Oomori Nishi, Tokyo 1438541, Japan

[9] Tokyo Womens Med Univ, Dept Pathol, Yachiyo Med Ctr, 477-96 Ohwadashinden, Yachiyo 2768524, Japan

[10] Funabashi Orthoped Hosp, 1-833 Hazama, Funabashi, Chiba 2740822, Japan

来源：

CELL DEATH & DISEASE | 2021年 / 12卷 / 07期

基金：

日本学术振兴会;

关键词：

THERAPY; CANCER; CELLS; KAP1; REPLICATION; VIROTHERAPY; MECHANISM; APOPTOSIS; PATHWAYS; ONYX-015;

D O I：

10.1038/s41419-021-03934-y

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

引用

页数：10