Inhibition of cathepsin K sensitizes oxaliplatin-induced apoptotic cell death by Bax upregulation through OTUB1-mediated p53 stabilization in vitro and in vivo

被引：13

作者：

Seo, Seung Un ^{[1
]}

Woo, Seon Min ^{[1
]}

Kim, Shin ^{[1
]}

Park, Jong-Wook ^{[1
]}

Lee, Hyun-Shik ^{[2
]}

Bae, Young-Seuk ^{[2
]}

Kim, Sang Hyun ^{[3
]}

Im, Seung-Soon ^{[4
]}

Seo, Ji Hae ^{[5
]}

Min, Kyoung-Jin ^{[6
]}

Kwon, Taeg Kyu ^{[1
,7
]}

机构：

[1] Keimyung Univ, Sch Med, Dept Immunol, Daegu 42601, South Korea

[2] Kyungpook Natl Univ, Coll Nat Sci, Sch Life Sci, BK21 Plus KNU Creat BioRes Grp, Daegu 41566, South Korea

[3] Kyungpook Natl Univ, Sch Med, Dept Pharmacol, Daegu 41944, South Korea

[4] Keimyung Univ, Sch Med, Dept Physiol, Daegu 42601, South Korea

[5] Keimyung Univ, Sch Med, Dept Biochem, Daegu 42601, South Korea

[6] Daegu Gyeongbuk Med Innovat Fdn DGMIF, New Drug Dev Ctr, Daegu 41061, South Korea

[7] Keimyung Univ, Ctr Forens Pharmaceut Sci, Daegu 42601, South Korea

来源：

ONCOGENE | 2022年 / 41卷 / 04期

基金：

新加坡国家研究基金会;

关键词：

TUMOR-SUPPRESSOR P53; MEMBRANE PERMEABILIZATION; EXPRESSION; BCL-2;

D O I：

10.1038/s41388-021-02088-7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cathepsin K is highly expressed in various types of cancers. However, the effect of cathepsin K inhibition in cancer cells is not well characterized. Here, cathepsin K inhibitor (odanacatib; ODN) and knockdown of cathepsin K (siRNA) enhanced oxaliplatin-induced apoptosis in multiple cancer cells through Bax upregulation. Bax knockdown significantly inhibited the combined ODN and oxaliplatin treatment-induced apoptotic cell death. Stabilization of p53 by ODN played a critical role in upregulating Bax expression at the transcriptional level. Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. Interestingly, ODN-induced p53 and Bax upregulation were modulated by the production of mitochondrial reactive oxygen species (ROS). Mitochondrial ROS scavengers prevented OTUB1-mediated p53 stabilization and Bax upregulation by ODN. These in vitro results were confirmed by in mouse xenograft model, combined treatment with ODN and oxaliplatin significantly reduced tumor size and induced Bax upregulation. Furthermore, human renal clear carcinoma (RCC) tissues revealed a strong correlation between phosphorylation of OTUB1(Ser16) and p53/Bax expression. Our results demonstrate that cathepsin K inhibition enhances oxaliplatin-induced apoptosis by increasing OTUB1 phosphorylation via CK2 activation, thereby promoting p53 stabilization, and hence upregulating Bax.

引用

页码：550 / 559

页数：10