title: Protein kinase Cα inhibitor protects against downregulation of claudin-1 during epithelial-mesenchymal transition of pancreatic cancer.
abstract: Protein kinase Cα (PKCα) is highly expressed in pancreatic cancer. However, the effects of PKCα on Snail and claudin-1, which play crucial roles in epithelial cell polarity during epithelial-mesenchymal transition (EMT), remain unclear. In this study, we investigated the mechanisms of regulation of Snail and claudin-1 via a PKCα signal pathway during EMT in pancreatic cancer cells and in normal human pancreatic duct epithelial cells (HPDEs). By immunostaining, overexpression of PKCα and downregulation of claudin-1 were observed in poorly differentiated human pancreatic cancer tissues and the pancreatic cancer cell line PANC-1. Treatment with the PKCα inhibitor Gö6976 transcriptionally decreased Snail and increased claudin-1 in PANC-1 cells. The PKCα inhibitor prevented upregulation of Snail and downregulation of claudin-1 during EMT induced by transforming growth factor-β1 (TGF-β1) treatment and under hypoxia in PANC-1 cells. The effects of the PKCα inhibitor were in part regulated via an extracellular signal-regulated kinase (ERK) signaling pathway. The PKCα inhibitor also prevented downregulation of the barrier function and fence function during EMT in well-differentiated pancreatic cancer cell line HPAC. In normal HPDEs, the PKCα inhibitor transcriptionally induced not only claudin-1 but also claudin-4, -7 and occludin without a change of Snail. Treatment with the PKCα inhibitor in normal HPDEs prevented downregulation of claudin-1 and occludin by TGF-β1 treatment and enhanced upregulation of claudin-1, -4, -7 and occludin under hypoxia. These findings suggest that PKCα regulates claudin-1 via Snail- and mitogen-activated protein kinase/ERK-dependent pathways during EMT in pancreatic cancer. Thus, PKCα inhibitors may be potential therapeutic agents against the malignancy of human pancreatic cancer cells.
authors: Department of Surgery, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.
authors: Daisuke
authors: D
authors: Kyuno
authors: Takashi
authors: T
authors: Kojima
authors: Hiroshi
authors: H
authors: Yamaguchi
authors: Tatsuya
authors: T
authors: Ito
authors: Yasutoshi
authors: Y
authors: Kimura
authors: Masafumi
authors: M
authors: Imamura
authors: Akira
authors: A
authors: Takasawa
authors: Masaki
authors: M
authors: Murata
authors: Satoshi
authors: S
authors: Tanaka
authors: Koichi
authors: K
authors: Hirata
authors: Norimasa
authors: N
authors: Sawada
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D062445:Claudin-1 / Q000096:biosynthesis*; D062506:Claudin-4 / Q000096:biosynthesis; D057167:Claudins / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D062793:Occludin / Q000096:biosynthesis; D010183:Pancreatic Ducts / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002070:Butadienes; D002227:Carbazoles; D062445:Claudin-1; D062506:Claudin-4; D057167:Claudins; C524370:Cldn7 protein, rat; D004791:Enzyme Inhibitors; D009570:Nitriles; D062793:Occludin; D034741:RNA, Small Interfering; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C113580:U 0126; C081021:Go 6976; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases