title: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and PH domain and leucine-rich repeat phosphatase cross-talk (PHLPP) in cancer cells and in transforming growth factor β-activated stem cells.
abstract: Akt kinase controls cell survival, proliferation, and invasive growth and is a critical factor for cancer development. Here we describe a cross-talk 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 the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) overexpression down-regulated PH domain and leucine-rich repeat phosphatase (PHLPP) and that PHLPP overexpression down-regulated PTEN. We also show that silencing PTEN by siRNA increased the levels of PHLPPs. This cross-talk 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-β1 induced cross-talk concomitant with epithelial-mesenchymal transition in stem cells. The cross-talk emerged as an integrated part of epithelial-mesenchymal transition. We conclude that cross-talk between PTEN and PHLPPs is silenced in normal prostate cells but activated in TGF-β1 transformed prostate stem and cancer cells and facilitates invasive growth.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden. Electronic address: aram.ghalali@ki.se.
authors.forename: Aram
authors.initials: A
authors.lastname: Ghalali
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Ye
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Högberg
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Stenius
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D044127:Epigenesis, Genetic; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D009687:Nuclear Proteins; D016212:Transforming Growth Factor beta; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Akt; PHLPP1; PHLPP2; PTEN; Prostate Cancer; Protein Phosphatase; Stem Cells