Abstract
Chronic activation of the phosphoinositide 3-kinase (PI3K)/PTEN signal transduction pathway contributes to metastatic cell growth, but up to now effectors mediating this response are poorly defined. By simulating chronic activation of PI3K signaling experimentally, combined with three-dimensional (3D) culture conditions and gene expression profiling, we aimed to identify novel effectors that contribute to malignant cell growth. Using this approach we identified and validated PKN3, a barely characterized protein kinase C-related molecule, as a novel effector mediating malignant cell growth downstream of activated PI3K. PKN3 is required for invasive prostate cell growth as assessed by 3D cell culture assays and in an orthotopic mouse tumor model by inducible expression of short hairpin RNA (shRNA). We demonstrate that PKN3 is regulated by PI3K at both the expression level and the catalytic activity level. Therefore, PKN3 might represent a preferred target for therapeutic intervention in cancers that lack tumor suppressor PTEN function or depend on chronic activation of PI3K.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basement Membrane / enzymology
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Basement Membrane / metabolism
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Basement Membrane / pathology
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Catalysis
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Cell Division
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Cell Line, Tumor
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Cell Transformation, Neoplastic
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Disease Models, Animal
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Enzyme Activation
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Gene Expression Regulation, Neoplastic
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Humans
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Lymphatic Metastasis
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Male
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Mice
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Mice, Knockout
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Prostatic Neoplasms / enzymology*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / pathology*
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Protein Kinase C / genetics
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Protein Kinase C / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein Tyrosine Phosphatases / deficiency
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Up-Regulation
Substances
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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protein kinase N
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Protein Kinase C
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Protein Tyrosine Phosphatases
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PTEN Phosphohydrolase
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Pten protein, mouse