KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer

被引：49

作者：

Gao, Lin ^{[1
,2
]}

Zhang, Wenbo ^{[1
,2
]}

Zhang, Jing ^{[3
]}

Liu, Junmei ^{[4
]}

Sun, Feifei ^{[1
,2
]}

Liu, Hui ^{[1
,2
]}

Hu, Jing ^{[1
,2
]}

Wang, Xin ^{[1
,2
]}

Wang, Xueli ^{[5
]}

Su, Peng ^{[6
]}

Chen, Shouzhen ^{[7
]}

Qu, Sifeng ^{[7
]}

Shi, Benkang ^{[7
]}

Xiong, Xueting ^{[8
]}

Chen, Weiwen ^{[4
]}

Dong, Xuesen ^{[9
,10
]}

Han, Bo ^{[1
,2
,6
]}

机构：

[1] Shandong Univ, Key Lab Expt Teratol, Minist Educ, Jinan 250012, Shandong, Peoples R China

[2] Shandong Univ, Dept Pathol, Sch Basic Med Sci, Cheeloo Coll Med, Jinan 250012, Shandong, Peoples R China

[3] Shandong First Med Univ, Shandong Prov Hosp, Dept Pharm, Jinan, Shandong, Peoples R China

[4] Shandong Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Cheeloo Coll Med, Jinan, Shandong, Peoples R China

[5] Binzhou City Cent Hosp, Dept Pathol, Binzhou, Peoples R China

[6] Shandong Univ, Dept Pathol, Cheeloo Coll Med, Qilu Hosp, Jinan, Shandong, Peoples R China

[7] Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Dept Urol, Jinan, Shandong, Peoples R China

[8] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[9] Vancouver Gen Hosp, Vancouver Prostate Ctr, Vancouver, BC, Canada

[10] Univ British Columbia, Dept Urol Sci, Vancouver, BC, Canada

来源：

CANCER RESEARCH | 2021年 / 81卷 / 04期

基金：

中国国家自然科学基金;

关键词：

ANDROGEN-RECEPTOR; TRANSCRIPTIONAL PROGRAM; PROTEIN; PROLIFERATION; ABIRATERONE; KINESIN-12; SURVIVAL; GROWTH; DRIVE; ERK;

D O I：

10.1158/0008-5472.CAN-20-1965

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not filly defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target. Significance: These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.

引用

页码：1026 / 1039

页数：14

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