Overexpression of transforming growth factor β1 in malignant prostate cells is partly caused by a runaway of TGF-β1 Auto-induction mediated through a defective recruitment of protein phosphatase 2A by TGF-β type i receptor

Nengwang Yu, James M. Kozlowski, Irwin I. Park, Lin Chen, Qiang Zhang, Danfeng Xu, Jennifer A. Doll, Susan E. Crawford, Charles B. Brendler, Chung Lee*

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Objectives: To elucidate the mechanism of transforming growth factor (TGF)β1 overexpression in prostate cancer cells. Methods: Malignant (PC3, DU145) and benign (RWPE1, BPH1) prostate epithelial cells were used. Phosphatase activity was measured using a commercial kit. Recruitment of the regulatory subunit, Bα, of protein phosphatase 2A (PP2A-Bα) by TGF-β type I receptor (TβRI) was monitored by coimmunoprecipitation. Blockade of TGF-β1 signaling in cells was accomplished either by using TGF-β-neutralizing monoclonal antibody or by transduction of a dominant negative TGF-β type II receptor retroviral vector. Results: Basal levels of TGF-β1 in malignant cells were significantly higher than those in benign cells. Blockade of TGF-β signaling resulted in a significant decrease in TGF-β1 expression in malignant cells, but not in benign cells. Upon TGF-β1 treatment (10 ng/mL), TGF-β1 expression was increased in malignant cells, but not in benign cells. This differential TGF-β1 auto-induction between benign and malignant cells correlated with differential activation of extracellular signal-regulated kinase (ERK). Following TGF-β1 treatment, the activity of serine/threonine phosphatase and recruitment of PP2A-Bα by TβRI increased in benign cells, but not in malignant cells. Inhibition of PP2A in benign cells resulted in an increase in ERK activation and in TGF-β1 auto-induction after TGF-β1 (10 ng/mL) treatment. Conclusions: These results suggest that TGF-β1 overexpression in malignant cells is caused, at least in part, by a runaway of TGF-β1 auto-induction through ERK activation because of a defective recruitment of PP2A-Bα by TβRI.

Original languageEnglish (US)
Pages (from-to)1519.e8-1519.e13
JournalUrology
Volume76
Issue number6
DOIs
StatePublished - Dec 2010

ASJC Scopus subject areas

  • Urology

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