Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication

Autor: Tobias Forster, Li Liu, Michelle Nessling, Orkhan Isayev, Wolfgang Gross, Sabrina Labsch, Martha Maria Gebhard, Ingrid Herr, Vanessa Rausch, Karsten Richter, Clarissa Gerhäuser, Jury Gladkich, Katharina Heilmann, Michael Schaefer, Peter Schemmer, Yiyao Zhang, Clifford C. Nwaeburu, Frank Schoensiegel, Jens Werner, Nathalia A. Giese, Juergen Mattern
Rok vydání: 2014
Předmět:
Cellular pathology
Cell signaling
Cell
Blotting
Western
Apoptosis
Cell Communication
Biology
Adenocarcinoma
Deoxycytidine
Immunoenzyme Techniques
chemistry.chemical_compound
Pancreatic Cancer
Cancer stem cell
Isothiocyanates
Pancreatic cancer
Spheroids
Cellular
Cancer Stem Cells
medicine
Tumor Cells
Cultured
Anticarcinogenic Agents
Humans
Phosphorylation
RNA
Small Interfering
Pancreas
Cell Proliferation
Bioactive dietary agents
Kinase
Gap Junctions
medicine.disease
Molecular biology
Gemcitabine
Pancreatic Neoplasms
Microscopy
Electron
medicine.anatomical_structure
Oncology
chemistry
Drug Resistance
Neoplasm
Case-Control Studies
Connexin 43
Sulfoxides
Cancer research
cardiovascular system
sense organs
biological phenomena
cell phenomena
and immunity
Sulforaphane
Carcinoma
Pancreatic Ductal
Research Paper
Zdroj: Oncotarget
Scopus-Elsevier
ISSN: 1949-2553
Popis: // Tobias Forster 1,2,* , Vanessa Rausch 1,2,* , Yiyao Zhang, Orkhan Isayev 1,2 , Katharina Heilmann 3 , Frank Schoensiegel 1,2 , Li Liu 1,2 , Michelle Nessling 4 , Karsten Richter 4 , Sabrina Labsch 1,2 , Clifford C. Nwaeburu 1,2 , Juergen Mattern 1,2 , Jury Gladkich 1,2 , Nathalia Giese 2 , Jens Werner 2 , Peter Schemmer 2 , Wolfgang Gross 1,2 , Martha M. Gebhard 1,2 , Clarissa Gerhauser 3 , Michael Schaefer 1,2 , Ingrid Herr 1,2 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 Correspondence: 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 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.
Databáze: OpenAIRE
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