title: Atypical protein kinase C zeta exhibits a proapoptotic function in ovarian cancer.
abstract: Intracellular signaling governed by serine/threonine kinases comprises the molecular interface between cell surface receptors and the nuclear transcriptional machinery. The protein kinase C (PKC) family members are involved in the control of many signaling processes directing cell proliferation, motility, and survival. Here, we examined a role of different PKC isoenzymes in protein phosphatase 2A (PP2A) and HRSL3 tumor suppressor-dependent cell death induction in the ovarian carcinoma cell line OVCAR-3. Phosphorylation and activity of PKC isoenzymes were measured in response to PP2A or phosphoinositide 3-kinase inhibition or HRSL3 overexpression. These experiments indicated a regulation of PKC, epsilon, zeta, and iota through PP2A and/or HRSL3, but not of PKCalpha and beta. Using isoform-specific peptide inhibitors and overexpression approaches, we verified a contribution to PP2A- and HRLS3-dependent apoptosis only for PKCzeta, suggesting a proapoptotic function of this kinase. We observed a significant proportion of human ovarian carcinomas expressing high levels of PKCzeta, which correlated with poor prognosis. Primary ovarian carcinoma cells isolated from patients also responded to okadaic acid treatment with increased phosphorylation of PKCzeta and apoptosis induction. Thus, our data indicate a contribution of PKCzeta in survival control in ovarian carcinoma cells and suggest that upregulation or activation of tyrosine kinase receptors in this tumor might impinge onto apoptosis control through the negative regulation of the atypical PKCzeta.
authors.affiliation: Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Hermann von Helmholtz Platz 1, Eggenstein-Leopoldshafen, Germany. irina.nazarenko@kit.edu
authors.forename: Irina
authors.initials: I
authors.lastname: Nazarenko
authors.forename: Marcel
authors.initials: M
authors.lastname: Jenny
authors.forename: Jana
authors.initials: J
authors.lastname: Keil
authors.forename: Cornelia
authors.initials: C
authors.lastname: Gieseler
authors.forename: Karen
authors.initials: K
authors.lastname: Weisshaupt
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.forename: Stefan
authors.initials: S
authors.lastname: Legewie
authors.forename: Lena
authors.initials: L
authors.lastname: Herbst
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
authors.forename: Florian
authors.initials: F
authors.lastname: Ueberall
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D054512:Phospholipases A2, Calcium-Independent; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology; D000099221:Protein Kinase C zeta
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D019319:Okadaic Acid; D054512:Phospholipases A2, Calcium-Independent; D011493:Protein Kinase C; D025521:Tumor Suppressor Proteins; D000099221:Protein Kinase C zeta; C490065:PLAAT3 protein, human