The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone

被引：213

作者：

Fournier, Pierrick G. J. ^{[1
,2
]}

Juarez, Patricia ^{[1
,2
]}

Jiang, Guanglong ^{[3
]}

Clines, Gregory A. ^{[2
,4
]}

Niewolna, Maria ^{[1
,2
]}

Kim, Hun Soo ^{[1
]}

Walton, Holly W. ^{[2
]}

Peng, Xiang Hong ^{[1
,2
]}

Liu, Yunlong ^{[3
]}

Mohammad, Khalid S. ^{[1
,2
]}

Wells, Clark D. ^{[5
]}

Chirgwin, John M. ^{[1
,2
,6
]}

Guise, Theresa A. ^{[1
,2
]}

机构：

[1] Indiana Univ Sch Med, Div Endocrinol, Indianapolis, IN 46202 USA

[2] Univ Virginia, Sch Med, Div Endocrinol, Charlottesville, VA 22903 USA

[3] Indiana Univ, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA

[4] Univ Michigan, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48105 USA

[5] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[6] Richard L Roudebush VA Med Ctr, Indianapolis, IN 46202 USA

来源：

CANCER CELL | 2015年 / 27卷 / 06期

基金：

美国国家卫生研究院;

关键词：

I KINASE INHIBITOR; GENE-EXPRESSION; NEDD4-BINDING PROTEIN; ANDROGEN RECEPTOR; TUMOR-CELLS; GROWTH; PATHWAYS; UBIQUITINATION; INVOLVEMENT; ACTIVATOR;

D O I：

10.1016/j.ccell.2015.04.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Transforming growth factor-beta (TGF-beta) regulates the expression of genes supporting breast cancer cells in bone, but little is known about prostate cancer bone metastases and TGF-beta. Our study reveals that the TGFBR1 inhibitor SD208 effectively reduces prostate cancer bone metastases. TGF-beta upregulates in prostate cancer cells a set of genes associated with cancer aggressiveness and bone metastases, and the most upregulated gene was PMEPA1. In patients, PMEPA1 expression decreased in metastatic prostate cancer and low Pmepa1 correlated with decreased metastasis-free survival. Only membrane-anchored isoforms of PMEPA1 interacted with R-SMADs and ubiquitin ligases, blocking TGF-beta signaling independently of the proteasome. Interrupting this negative feedback loop by PMEPA1 knockdown increased prometastatic gene expression and bone metastases in a mouse prostate cancer model.

引用

页码：809 / 821

页数：13

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