ER-Stress-Induced Differentiation Sensitizes Colon Cancer Stem Cells to Chemotherapy
Mattheus C.B. Wielenga,
Selcuk Colak,
Jarom Heijmans,
Jooske F. van Lidth de Jeude,
Hans M. Rodermond,
James C. Paton,
Adrienne W. Paton,
Louis Vermeulen,
Jan Paul Medema,
Gijs R. van den Brink
Affiliations
Mattheus C.B. Wielenga
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
Selcuk Colak
Laboratory of Experimental Oncology and Radiobiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
Jarom Heijmans
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
Jooske F. van Lidth de Jeude
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
Hans M. Rodermond
Laboratory of Experimental Oncology and Radiobiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
James C. Paton
Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia
Adrienne W. Paton
Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia
Louis Vermeulen
Laboratory of Experimental Oncology and Radiobiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
Jan Paul Medema
Laboratory of Experimental Oncology and Radiobiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
Gijs R. van den Brink
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
Colon cancer stem cells (colon-CSCs) are more resistant to conventional chemotherapy than differentiated cancer cells. This subset of therapy refractory cells is therefore believed to play an important role in post-therapeutic tumor relapse. In order to improve the rate of sustained response to conventional chemotherapy, development of approaches is warranted that specifically sensitize colon-CSCs to treatment. Here, we report that ER-stress-induced activation of the unfolded protein response (UPR) forces colon-CSCs to differentiate, resulting in their enhanced sensitivity to chemotherapy in vitro and in vivo. Our data suggest that agents that induce activation of the UPR may be used to specifically increase sensitivity of colon-CSCs to the effects of conventional chemotherapy.
