title: Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: involvement of protein kinase C-θ activation.
abstract: Associations between growth factor receptor-mediated cell signaling and cancer cell growth have been previously characterized. Receptors for prostaglandin E2, such as EP2, and EP4, play roles in cancer growth, progression and invasion. Thus, we examined the interactions between EP2/EP4- and IGF-1R-mediated cellular signaling in human pancreatic cancer cells. Selective antagonists against EP2 and EP4 abrogated IGF-1-stimulated cell growth and suppressed MEK/ERK phosphorylation. In subsequent experiments, phospho-antibody arrays indicated increased phosphorylation levels of protein kinase C-θ (PKC-θ) at the Thr538 position following the inhibition of EP2/EP4-mediated signaling. Inhibition of PKC-θ activity impaired cell viability compared with EP2/EP4-antagonized IGF-1-stimulated cells. PKC-θ kinase MAP4K3, which plays a pivotal role in PKC-θ activation, also affected growth signaling in the presence of EP2/EP4 antagonists. Administration of EP2 and EP4 antagonists significantly inhibited the growth of an orthotopic xenograft of IGF-1-secreting pancreatic cancer cells, with increased phospho-PKC-θ and decreased phospho-ERK. Clinico-pathological analyses showed that 17.4% of surgical pancreatic cancer specimens were quadruple-positive for IGF-1R, EP2 (or EP4), MAP4K3, and PKC-θ. These results indicate a novel signaling crosstalk between EP2/EP4 and IGF-1R in cancer cells, and suggest that the MAP4K3-PKC-θ axis is central and could be exploited as a molecular target for cancer therapy.
authors: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors: Tetsuyuki
authors: T
authors: Takahashi
authors: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors: Hisanori
authors: H
authors: Uehara
authors: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors: Hirohisa
authors: H
authors: Ogawa
authors: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors: Hitomi
authors: H
authors: Umemoto
authors: Division of Pathology, Tokushima University Hospital, Tokushima, Japan.
authors: Yoshimi
authors: Y
authors: Bando
authors: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors: Keisuke
authors: K
authors: Izumi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004347:Drug Interactions; D004789:Enzyme Activation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D054833:Isoindoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000187:drug effects; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D054833:Isoindoles; C515270:N-(2-(4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo(f)isoindol-2-yl)phenyl)acetyl)benzene sulphonamide; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D007334:Insulin-Like Growth Factor I; D051745:Protein Kinase C-delta
keywords: E-prostanoid receptor; insulin-like growth factor receptor-1; protein kinase C-θ
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