WLS-Wnt signaling promotes neuroendocrine prostate cancer

被引：38
作者：
Bland, Tyler [1 ,7 ]
Wang, Jing [1 ]
Yin, Lijuan [2 ]
Pu, Tianjie [1 ]
Li, Jingjing [1 ]
Gao, Jin [1 ]
Lin, Tzu-Ping [3 ,4 ,5 ]
Gao, Allen C. [6 ]
Wu, Boyang Jason [1 ]
机构：
[1] Washington State Univ, Coll Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Spokane, WA 99202 USA
[2] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Med, Urooncol Res Program, Los Angeles, CA 90048 USA
[3] Taipei Vet Gen Hosp, Dept Urol, Taipei 11217, Taiwan
[4] Natl Yang Ming Univ, Sch Med, Dept Urol, Taipei 11221, Taiwan
[5] Natl Yang Ming Univ, Shu Tien Urol Res Ctr, Taipei 11221, Taiwan
[6] Univ Calif Davis, Dept Urol Surg, Sacramento, CA 95817 USA
[7] Univ Idaho, WWAMI Med Educ Program, Moscow, ID 83844 USA
来源：
ISCIENCE | 2021年 / 24卷 / 01期
关键词：
KINASE-C-DELTA; STEM-CELLS; PATHWAY; DIFFERENTIATION; ENZALUTAMIDE; ACTIVATION; RESISTANCE; SECRETION; INHIBITION; WNTLESS;
D O I：
10.1016/j.isci.2020.101970
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Neuroendocrine prostate cancer (NEPC) is a lethal prostate cancer subtype arising as a consequence of more potent androgen receptor (AR) targeting in castration-resistant prostate cancer (CRPC). Its molecular pathogenesis remains elusive. Here, we report that the Wnt secretion mediator Wnt less (WLS) is a major driver of NEPC and aggressive tumor growth in vitro and in vivo. Mechanistic studies showed that WLS is a transcriptional target suppressed by AR that activates the ROR2/PKC delta/ERK signaling pathway to support the neuroendocrine (NE) traits and proliferative capacity of NEPC cells. Analysis of clinical samples and datasets revealed that WLS was highly expressed in CRPC and NEPC tumors. Finally, treatment with the Wnt secretion inhibitor LGK974 restricted NE prostate tumor xenograft growth in mice. These findings collectively characterize the contribution of WLS to NEPC pathogenesis and suggest that WLS is a potential therapeutic target in NEPC.
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页数：33
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