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SHR Neuro Krebs Kardio Lipid

Forster, T; Rausch, V; Zhang, Y; Isayev, O; Heilmann, K; Schoensiegel, F; Liu, L; Nessling, M; Richter, K; Labsch, S; Nwaeburu, CC; Mattern, J; Gladkich, J; Giese, N; Werner, J; Schemmer, P; Gross, W; Gebhard, MM; Gerhauser, C; Schaefer, M; Herr, I.
Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication.
Oncotarget. 2014; 5(6):1621-1634 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Schemmer Peter
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Number of Figures: 7
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Abstract:
The extreme aggressiveness of pancreatic ductal adenocarcinoma (PDA) has been associated with blocked gap junctional intercellular communication (GJIC) and the presence of cancer stem cells (CSCs). We examined whether disturbed GJIC is responsible for a CSC phenotype in established and primary cancer cells and patient tissue of PDA using interdisciplinary methods based in physiology, cell and molecular biology, histology and epigenetics. Flux of fluorescent dyes and gemcitabine through gap junctions (GJs) was intact in less aggressive cells but not in highly malignant cells with morphological dysfunctional GJs. Among several connexins, only Cx43 was expressed on the cell surface of less aggressive and GJIC-competent cells, whereas Cx43 surface expression was absent in highly malignant, E-cadherin-negative and GJIC-incompetent cells. The levels of total Cx43 protein and Cx43 phosphorylated at Ser368 and Ser279/282 were high in normal tissue but low to absent in malignant tissue. si-RNA-mediated inhibition of Cx43 expression in GJIC-competent cells prevented GJIC and induced colony formation and the expression of stem cell-related factors. The bioactive substance sulforaphane enhanced Cx43 and E-cadherin levels, inhibited the CSC markers c-Met and CD133, improved the functional morphology of GJs and enhanced GJIC. Sulforaphane altered the phosphorylation of several kinases and their substrates and inhibition of GSK3, JNK and PKC prevented sulforaphane-induced CX43 expression. The sulforaphane-mediated expression of Cx43 was not correlated with enhanced Cx43 RNA expression, acetylated histone binding and Cx43 promoter de-methylation, suggesting that posttranslational phosphorylation is the dominant regulatory mechanism. Together, the absence of Cx43 prevents GJIC and enhances aggressiveness, whereas sulforaphane counteracts this process, and our findings highlight dietary co-treatment as a viable treatment option for PDA.
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Adenocarcinoma - drug therapy
Adenocarcinoma - metabolism
Adenocarcinoma - pathology
Anticarcinogenic Agents - pharmacology
Apoptosis - drug effects
Blotting, Western -
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Case-Control Studies -
Cell Communication - drug effects
Cell Proliferation - drug effects
Connexin 43 - antagonists & inhibitors
Connexin 43 - genetics
Connexin 43 - metabolism
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Drug Resistance, Neoplasm - drug effects
Gap Junctions - drug effects
Gap Junctions - metabolism
Gap Junctions - pathology
Humans -
Immunoenzyme Techniques -
Isothiocyanates - pharmacology
Microscopy, Electron -
Pancreas - metabolism
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Phosphorylation - drug effects
RNA, Small Interfering - genetics
Spheroids, Cellular - drug effects
Spheroids, Cellular - metabolism
Spheroids, Cellular - pathology
Tumor Cells, Cultured -

Find related publications in this database (Keywords)
Cancer Stem Cells
Pancreatic Cancer
Bioactive dietary agents
Sulforaphane
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