title: Repressed PKCδ activation in glycodelin-expressing cells mediates resistance to phorbol ester and TGFβ.
abstract: Glycodelin is a glycoprotein mainly expressed in well-differentiated epithelial cells in reproductive tissues. In normal secretory endometrium, the expression of glycodelin is abundant and regulated by progesterone. In hormone-related cancers glycodelin expression is associated with well-differentiated tumors. We have previously found that glycodelin drives epithelial differentiation of HEC-1B endometrial adenocarcinoma cells, resulting in reduced tumor growth in a preclinical mouse model. Here we show that glycodelin-transfected HEC-1B cells have repressed protein kinase C delta (PKCδ) activation, likely due to downregulation of PDK1, and are resistant to phenotypic change and enhanced migration induced by phorbol 12-myristate 13-acetate (PMA). In control cells, which do not express glycodelin, the effects of PMA were abolished by using PKCδ and PDK1 inhibitors, and knockdown of PKCδ, MEK1 and 2, or ERK1 and 2 by siRNAs. Similarly, transforming growth factor β (TGFβ)-induced phenotypic change was only seen in control cells, not in glycodelin-producing cells, and it was mediated by PKCδ. Taken together, these results strongly suggest that PKCδ, via MAPK pathway, is involved in the glycodelin-driven cell differentiation rendering the cells resistant to stimulation by PMA and TGFβ.
authors.affiliation: Department of Clinical Chemistry, Medicum, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Hautala
authors.affiliation: Department of Clinical Chemistry, Medicum, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Koistinen
authors.affiliation: Department of Clinical Chemistry, Medicum, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland. Electronic address: hannu.k.koistinen@helsinki.fi.
authors.forename: Hannu
authors.initials: H
authors.lastname: Koistinen
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D000071816:Glycodelin / Q000378:metabolism*; D006801:Humans; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D000071816:Glycodelin; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate
keywords: Cell differentiation; Endometrial carcinoma; Glycodelin; MAPK pathway; PKCδ; TGFβ