Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells

Abstract

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 1α (IRE1α), an ER stress sensor, is a key component of UPR. However, the role of IRE1α in tumorigenesis remains unclear. The purpose of this work is to investigate the role of IRE1α in colon cancer and to determine whether IRE1α could serve as a target for therapy. We found that knockdown of IRE1α suppressed the proliferation of colon cancer cells in vitro and xenograft growth in vivo. Inhibition of expression of IRE1α decreased stemness of colon cancer stem cells (CSCs) and attenuated growth of intestinal organoids. Genetic ablation of IRE1α prevented the colitis-associated colonic tumorigenesis in mice. The mechanistic study indicates that knockdown of IRE1α repressed the expression of β-catenin, a key factor that drives colonic tumorigenesis, through activating pancreatic ER kinase/eukaryotic translation initiation factor 2α signaling. We found that the IRE1a-specific inhibitor 4μ8C could suppress the production of β-catenin, inhibited the proliferation of colon cancer cells, repressed colon CSCs and prevented xenograft growth. The results suggest that IRE1α has a critical role in colonic tumorigenesis and IRE1α targeting might be a strategy for treatment of colon cancers.

The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance

“…The IRE1‐XBP1s pathway has been linked to cell proliferation in several cancers including colon cancer, breast cancer, prostate cancer and melanoma. Knockdown of IRE1 expression in a panel of colon cancer cell lines reduced cell proliferation in vitro and in vivo [Li et al., ]. Similarly, inhibiting IRE1 RNase activity reduced the proliferation of breast cancer cells in vitro [Logue et al., ].…”

“…Similarly, inhibiting IRE1 RNase activity reduced the proliferation of breast cancer cells in vitro [Logue et al., ]. The observed reduction in proliferation was not associated with increased cell death but was linked in vitro to the arrest of cells in G1 [Li et al., , Logue et al., ], indicating IRE1 signalling can impact on cell cycle dynamics. The Cyclin D1:CDK4 complex promotes movement through the G1 phase of the cell cycle by inhibiting retinoblastoma protein.…”

“…To off‐set the stresses of ECM detachment, cells utilise adaptive pathways including the UPR (Figure ). Knockdown of XBP1 has been reported to reduce soft agar colony formation in a panel of breast cancer cell lines [Chen et al., ]; and in colon cancer cell lines, knockdown of IRE1 suppressed sphere formation and reduced growth of intestinal organoids [Li et al., ]. Likewise, PERK signalling has also been linked to cell survival following ECM detachment, with PERK‐eIF2α‐ATF4‐CHOP signalling co‐ordinating autophagy induction and oxidative stress relief [Avivar‐Valderas et al., ].…”

The multiple roles of the unfolded protein response regulator IRE1α in cancer

“…In in vitro organoid cultures as well as mouse xenograft models of colon cancer, knockdown of IRE1α reduces colon cancer by simultaneous suppression of β-catenin translation and RNase dependent activation of the PERK signaling. 50 Similarly, expression of a dominant negative form of IRE1α in the U87 glioblastoma cell line reduced proliferation in vitro and tumor growth in xenografts. 51,52 This was associated with upregulation of extracellular matrix protein genes and enhanced expression of SPARC, an antiangiogenic protein and a target of RIDD, as well as downregulation of proinflammatory and proangiogenic factors vascular endothelial growth factor A and interleukin-6 (IL-6).…”

“…While some consensus cleavage sites have been identified for mRNAs and miRNAs degraded by RIDD, the targets for this more promiscuous RNase activity may be cell and context specific as the effects will vary according to the nature of the transcript degraded. In in vitro organoid cultures as well as mouse xenograft models of colon cancer, knockdown of IRE1α reduces colon cancer by simultaneous suppression of β‐catenin translation and RNase dependent activation of the PERK signaling . Similarly, expression of a dominant negative form of IRE1α in the U87 glioblastoma cell line reduced proliferation in vitro and tumor growth in xenografts .…”