PTEN and PHLPP Crosstalk in Cancer Cells and in TGF{beta}-Activated Stem Cells [Signal Transduction]

March 5th, 2014 by Ghalali, A., Ye, Z.–W., Hogberg, J., Stenius, U.

Akt kinase controls cell survival, proliferation and invasive growth and is a critical factor for cancer development. Here we describe a crosstalk between phosphatases that may preserve levels of activated/phosphorylated Akt and confer aggressive growth of cancer cells. In prostatic cancer cells, but not in non-transformed cells or in prostate stem cells, we found that PTEN overexpression down-regulated PHLPP and that PHLPP overexpression down-regulated PTEN. We also show that silencing PTEN by siRNA increased the levels of PHLPPs. This crosstalk facilitated invasive migration and was mediated by epigenetic alterations, including activation of miR-190, miR-214, polycomb group of proteins as well as DNA methylation. A role for the purinergic receptor P2X4, previously associated with wound healing, was indicated. We also show that TGF-β induced crosstalk concomitant with epithelial-mesenchymal transition (EMT) in stem cells. The crosstalk emerged as an integrated part of EMT. We conclude that crosstalk between PTEN and PHLPPs is silenced in normal prostate cells but activated in TGF-β-transformed in prostate stem and in cancer cells and facilitates invasive growth.