Regulation of the Tumor Suppressor PTEN through Exosomes: A Diagnostic Potential for Prostate Cancer

Kathleen Gabriel,Fadwa Majeed,Khalid Al-Nedawi,Talha Qureshi,Alistair Ingram,Anil Kapoor,Damu Tang,Richard Austin,Surinder K Batra

doi:10.1371/journal.pone.0070047

Kathleen Gabriel, Fadwa Majeed + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0070047

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Journal: PLoS ONE	Publication Date: Jul 25, 2013
Citations: 112	License type: CC BY 4.0

Affiliation: McMaster University, St. Joseph's Hospital

Abstract

PTEN is a potent tumor-suppressor protein. Aggressive and metastatic prostate cancer (PC) is associated with a reduction or loss of PTEN expression. PTEN reduction often occurs without gene mutations, and its downregulation is not fully understood. Herein, we show that PTEN is incorporated in the cargo of exosomes derived from cancer cells. PTEN is not detected in exosomes derived from normal, noncancerous cells. We found that PTEN can be transferred to other cells through exosomes. In cells that have a reduction or complete loss of PTEN expression, the transferred PTEN is competent to confer tumor-suppression activity to acceptor cells. In PC patients, we show that PTEN is incorporated in the cargo of exosomes that circulate in their blood. Interestingly, normal subjects have no PTEN expression in their blood exosomes. Further, we found that the prostate-specific antigen (PSA) is incorporated in PC patients’ and normal subjects’ blood exosomes. These data suggest that exosomal PTEN can compensate for PTEN loss in PTEN deficient cells, and may have diagnostic value for prostate cancer.

Highlights

Prostate cancer (PC) is the most frequently diagnosed cancer and the second highest cause of cancer-related deaths in men [1,2,3]
We determined the status of presence of exosomal content (PTEN) in the following PC cells: DU145, DU145 stably transfected with PTEN siRNA (DU145Kd) for PTEN downregulation or knockdown, and DU145 transfected with control siRNA [12]
Both DU145 cells with PTEN knockdown (DU145Kd) cells (Figure 1A) and exosomes (Figure 1B) showed a downregulation of PTEN expression compared to the wild type DU145 cells and DU145 cells transfected with control siRNA

Summary

Introduction

Prostate cancer (PC) is the most frequently diagnosed cancer and the second highest cause of cancer-related deaths in men [1,2,3]. The loss of one copy of the PTEN gene contributes to prostate tumor initiation, while further reduction in PTEN expression supports the invasion and metastatic behavior of PC [4]. The main lipid substrate of PTEN is phosphatidylinositol (3,4,5) triphosphate (PIP-3). The main mechanism of tumor suppression by PTEN is the maintenance of cellular PIP-3 at low levels, inhibiting the PI3K-AKT pathway and contributing to cellular apoptosis or cell cycle arrest [5]. The reduction of PTEN protein expression often occurs in the absence of gene mutations [6,7,8]. Different mechanisms contributing to the reduction of PTEN expression in tumors have been identified, including promoter methylation [10,11], and negative regulator proteins [12]. Our results point to a new mechanism by which cancer cells regulate PTEN expression through exosomes

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