Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication
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Tobias Forster1,2,*, Vanessa Rausch1,2,*, Yiyao Zhang, Orkhan Isayev1,2, Katharina Heilmann3, Frank Schoensiegel1,2, Li Liu1,2, Michelle Nessling4, Karsten Richter4, Sabrina Labsch1,2, Clifford C. Nwaeburu1,2, Juergen Mattern1,2, Jury Gladkich1,2, Nathalia Giese2, Jens Werner2, Peter Schemmer2, Wolfgang Gross1,2, Martha M. Gebhard1,2, Clarissa Gerhauser3, Michael Schaefer1,2, Ingrid Herr1,2
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
* These authors contributed equally to this work
Ingrid Herr, email:
Keywords: Cancer Stem Cells, Pancreatic Cancer, Bioactive dietary agents, Sulforaphane
Received: January 3, 2014 Accepted: January 20, 2014 Published: January 22, 2014
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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