Epithelial-mesenchymal transition induces endoplasmic-reticulum-stress response in human colorectal tumor cells.
Tumor cells are stressed by unfavorable environmental conditions like hypoxia or starvation. Driven by the resulting cellular stress tumor cells undergo epithelial-mesenchymal transition. Additionally, cellular stress is accompanied by endoplasmic reticulum-stress which induces an unfolded protein response. It is unknown if epithelial-mesenchymal transition and endoplasmic reticulum-stress are occurring as independent parallel events or if an interrelationship exists between both of them. Here, we show that in colorectal cancer cells endoplasmic reticulum-stress depends on the induction of ZEB-1, which is a main factor of epithelial-mesenchymal transition. In the absence of ZEB-1 colorectal cancer cells cannot mount endoplasmic reticulum-stress as a reaction on cellular stress situations like hypoxia or starvation. Thus, our data suggest that there is a hierarchy in the development of cellular stress which starts with the presence of environmental stress that induces epithelial-mesenchymal transition which allows finally endoplasmic reticulum-stress. This finding highlights the central role of epithelial-mesenchymal transition during the process of tumorigenesis as epithelial-mesenchymal transition is also associated with chemoresistance and cancer stemness. Consequently, endoplasmic reticulum-stress might be a well suited target for chemotherapy of colorectal cancers.
Institute of Pathology, University of Munich, Munich, Germany.
Evelyn
E
Zeindl-Eberhart
Institute of Pathology, University of Munich, Munich, Germany.
Lydia
L
Brandl
Institute of Pathology, University of Munich, Munich, Germany.
Sibylle
S
Liebmann
Institute of Pathology, University of Munich, Munich, Germany.
Steffen
S
Ormanns
Institute of Pathology, University of Munich, Munich, Germany.
Silvio K
SK
Scheel
Department of Visceral Surgery, University of Freiburg, Freiburg, Germany.
Thomas
T
Brabletz
Institute of Pathology, University of Munich, Munich, Germany.
Thomas
T
Kirchner
Institute of Pathology, University of Munich, Munich, Germany.
Andreas
A
Jung
D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1