ER-Stress-Induced Differentiation Sensitizes Colon Cancer Stem Cells to Chemotherapy

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. [Display omitted] •Colon-CSCs are more resistant to chemotherapy than differentiated cancer cells•Activation of the unfolded protein response causes differentiation of colon-CSCs•UPR-induced differentiation enhances response to chemotherapy in vitro and in vivo Colon cancer stem cells (colon-CSCs) are more resistant to chemotherapy than differentiated cancer cells. Wielenga et al. show that activation of the unfolded protein response (UPR) forces colon-CSCs to differentiate, which augments their sensitivity to conventional chemotherapy.