title: Sustained Akt Activity Is Required to Maintain Cell Viability in Seborrheic Keratosis, a Benign Epithelial Tumor.
abstract: Seborrheic keratoses (SKs) are common benign skin tumors that share many morphological features with their malignant counterpart, squamous cell carcinoma. SKs frequently have acquired oncogenic mutations in the receptor tyrosine kinase/phosphatidylinositol 3-kinase/Akt signaling cascade. We developed a reliable culture system to study SKs in vitro and screened these cells using a library of selective kinase inhibitors to evaluate effects on cell survival. These benign tumors are sensitive to inhibition by ATP-competitive Akt inhibitors, including A-443654 and GSK690693. RNA interference-mediated Akt suppression mimicked the effects of enzyme inhibition in cultured cells. Akt inhibition suppressed phosphorylation of downstream targets of Akt kinase that are critical for cell survival, including MDM2 and FOXO3a, and induced apoptosis. Cell death was also dependent on p53, mutations in which, although common in cutaneous squamous cell carcinoma, have not been identified in SKs. Intact explants of SKs were also sensitive to Akt inhibition. In addition to the obvious therapeutic implications of these findings, identifying the signaling characteristics that differentiate benign and malignant tumors may inform our understanding of the malignant state.
authors.affiliation: Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: VNEEL@partners.org.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Neel
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Todorova
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Eunjeong
authors.initials: E
authors.lastname: Kwon
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Minjeong
authors.initials: M
authors.lastname: Kang
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Nathanael
authors.initials: N
authors.lastname: Gray
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. Electronic address: amandinova@mgh.harvard.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Mandinova
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002470:Cell Survival / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D006801:Humans; D007150:Immunohistochemistry; D017492:Keratosis, Seborrheic / Q000235:genetics / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D012878:Skin Neoplasms / Q000473:pathology
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051057:Proto-Oncogene Proteins c-akt