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

Pierrick G J Fournier; Patricia Juárez; Guanglong Jiang; Gregory A Clines; Maria Niewolna; Hun Soo Kim; Holly W Walton; Xiang Hong Peng; Yunlong Liu; Khalid S Mohammad; Clark D Wells; John M Chirgwin; Theresa A Guise

doi:10.1016/j.ccell.2015.04.009

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

Cancer Cell. 2015 Jun 8;27(6):809-21. doi: 10.1016/j.ccell.2015.04.009. Epub 2015 May 14.

Affiliations

¹ Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
² Center for Computational Biology and Bioinformatics, Indiana University, Indianapolis, IN 46202, USA.
³ Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48105, USA.
⁴ Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁵ Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
⁶ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁷ Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA.
⁸ Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA. Electronic address: tguise@iu.edu.

Abstract

Transforming growth factor-β (TGF-β) regulates the expression of genes supporting breast cancer cells in bone, but little is known about prostate cancer bone metastases and TGF-β. Our study reveals that the TGFBR1 inhibitor SD208 effectively reduces prostate cancer bone metastases. TGF-β 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-β 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bone Neoplasms / genetics
Bone Neoplasms / metabolism
Bone Neoplasms / prevention & control
Bone Neoplasms / secondary*
COS Cells
Cell Line, Tumor
Chlorocebus aethiops
Disease Models, Animal
Gene Knockdown Techniques
Hep G2 Cells
Humans
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Nude
Prostatic Neoplasms / drug therapy
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology*
Pteridines / pharmacology
Signal Transduction
Transforming Growth Factor beta / antagonists & inhibitors
Transforming Growth Factor beta / metabolism*

Substances

Membrane Proteins
PMEPA1 protein, human
Pteridines
SD-208
Transforming Growth Factor beta

Associated data

GEO/GSE58698

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding