Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication
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...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2014 Jan 22
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| In: |
OncoTarget
Year: 2014, Volume: 5, Issue: 6, Pages: 1621-1634 |
| ISSN: | 1949-2553 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039235/
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| Author Notes: | Tobias Forster, Vanessa Rausch, Yiyao Zhang, Orkhan Isayev, Katharina Heilmann, Frank Schoensiegel, Li Liu, Michelle Nessling, Karsten Richter, Sabrina Labsch, Clifford C. Nwaeburu, Juergen Mattern, Jury Gladkich, Nathalia Giese, Jens Werner, Peter Schemmer, Wolfgang Gross, Martha M. Gebhard, Clarissa Gerhauser, Michael Schaefer, Ingrid Herr |
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| 245 | 1 | 0 | |a Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication |c Tobias Forster, Vanessa Rausch, Yiyao Zhang, Orkhan Isayev, Katharina Heilmann, Frank Schoensiegel, Li Liu, Michelle Nessling, Karsten Richter, Sabrina Labsch, Clifford C. Nwaeburu, Juergen Mattern, Jury Gladkich, Nathalia Giese, Jens Werner, Peter Schemmer, Wolfgang Gross, Martha M. Gebhard, Clarissa Gerhauser, Michael Schaefer, Ingrid Herr |
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| 520 | |a 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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