| First Author | Li XX | Year | 2017 |
| Journal | Oncogene | Volume | 36 |
| Issue | 48 | Pages | 6738-6746 |
| PubMed ID | 28825721 | Mgi Jnum | J:251029 |
| Mgi Id | MGI:6101143 | Doi | 10.1038/onc.2017.284 |
| Citation | Li XX, et al. (2017) Knockdown of IRE1alpha inhibits colonic tumorigenesis through decreasing beta-catenin and IRE1alpha targeting suppresses colon cancer cells. Oncogene 36(48):6738-6746 |
| abstractText | The endoplasmic reticulum (ER) stress occurs frequently in cancers. The unfolded protein response (UPR) is activated to cope with ER stress. This has generated widespread interest in targeting UPR as therapeutic strategies. Inositol-requiring transmembrane kinase/endonuclease 1alpha (IRE1alpha), an ER stress sensor, is a key component of UPR. However, the role of IRE1alpha in tumorigenesis remains unclear. The purpose of this work is to investigate the role of IRE1alpha in colon cancer and to determine whether IRE1alpha could serve as a target for therapy. We found that knockdown of IRE1alpha suppressed the proliferation of colon cancer cells in vitro and xenograft growth in vivo. Inhibition of expression of IRE1alpha decreased stemness of colon cancer stem cells (CSCs) and attenuated growth of intestinal organoids. Genetic ablation of IRE1alpha prevented the colitis-associated colonic tumorigenesis in mice. The mechanistic study indicates that knockdown of IRE1alpha repressed the expression of beta-catenin, a key factor that drives colonic tumorigenesis, through activating pancreatic ER kinase/eukaryotic translation initiation factor 2alpha signaling. We found that the IRE1a-specific inhibitor 4mu8C could suppress the production of beta-catenin, inhibited the proliferation of colon cancer cells, repressed colon CSCs and prevented xenograft growth. The results suggest that IRE1alpha has a critical role in colonic tumorigenesis and IRE1alpha targeting might be a strategy for treatment of colon cancers. |
