Regulation of the tumour suppressor PTEN through exosomes

Abstract

<p>PTEN is a potent tumour 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, and this is an exclusive characteristic of cancer cells; normal cells do not incorporate PTEN in their exosomes. We found that this process is affected by the expression of oncogenes, with activation of oncogenic molecules leading to increased PTEN incorporation into exosomes. PTEN expressed in exosomes can be transferred to other cells that have a reduction or loss of PTEN expression. The transferred PTEN is active, as cells showed a substantial increase in phosphatase activity upon treatment with PTEN-bearing exosomes. PTEN transferred through exosomes is also competent to confer tumour-suppression activity to acceptor cells. After incubation with PTEN-bearing exosomes, recipient cells exhibited decreased AKT phosphorylation, changes in the expression of cell cycle mediators indicating cell cycle arrest, and decreased proliferation. These data suggest that exosomal PTEN may be able to compensate for PTEN loss in cancer cells, by transferring the active protein to cancer cells where it can then perform its role as a tumour suppressor.</p>