Sulforaphane counteracts aggressiveness of pancreatic cancer driven by
dysregulated Cx43-mediated gap junctional intercellular communication |
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| Authors: | 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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| Institution: | 1. General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany;2. Experimental Surgery, University of Heidelberg, Heidelberg, Germany;3. Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany;4. Core Facility Electron Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany |
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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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| Keywords: | Cancer Stem Cells Pancreatic Cancer Bioactive dietary agents Sulforaphane |
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