Heterozygosity of Chaperone Grp78 Reduces Intestinal Stem Cell Regeneration Potential and Protects against Adenoma Formation

Abstract

Deletion of endoplasmic reticulum resident chaperone Grp78 results in activation of the unfolded protein response and causes rapid depletion of the entire intestinal epithelium. Whether modest reduction of Grp78 may affect stem cell fate without compromising intestinal integrity remains unknown. Here, we employ a model of epithelial-specific, heterozygous deletion by use of mice and organoids. We examine models of irradiation and tumorigenesis, both and Although we observed no phenotypic changes in heterozygous mice, heterozygous organoid growth was markedly reduced. Irradiation of heterozygous mice resulted in less frequent regeneration of crypts compared with nonrecombined (wild-type) mice, exposing reduced capacity for self-renewal upon genotoxic insult. We crossed mice to-mutant animals for adenoma studies and found that adenomagenesis in heterozygous- heterozygous mice was reduced compared with heterozygous controls (1.43 vs. 3.33; < 0.01). In conclusion, epithelium-specific heterozygosity compromises epithelial fitness under conditions requiring expansive growth such as adenomagenesis or regeneration after γ-irradiation. These results suggest that Grp78 may be a therapeutic target in prevention of intestinal neoplasms without affecting normal tissue. Heterozygous disruption of chaperone protein Grp78 reduces tissue regeneration and expansive growth and protects from tumor formation without affecting intestinal homeostasis. .

Omega-3 Fatty Acid-Enriched Fish Oil and Selenium Combination Modulates Endoplasmic Reticulum Stress Response Elements and Reverses Acquired Gefitinib Resistance in HCC827 Lung Adenocarcinoma Cells

“…A recent study by van Lidth de Jeude et al proposed that GRP78 may be a therapeutic target for the prevention of intestinal neoplasms without affecting normal tissue [ 47 ]. Based on their study in mice, Lee et al described a notion that a normal organ requires only a low basal GRP78 level for function maintenance, while cancer cells require high levels of GRP78 for survival, growth, invasion, and treatment resistance [ 48 ].…”

“…By contrast, the viability of MRC-5 (fetal lung fibroblast) cells was unsusceptible to the combination effect of FO and Se [ 31 ]. These studies suggest that targeting GRP78 for the treatment of cancer is unlikely to have major deleterious side effects [ 31 , 47 , 48 , 49 ]. An elevated GRP78 level has been linked to the acquired resistance of cancer cells to tamoxifen [ 50 ], 5-fluorouracil (5-FU) [ 51 ], gemcitabine [ 52 ], and targeted therapy agents such as sorafenib [ 53 ] and sunitinib [ 54 ].…”

Endoplasmic reticulum stress regulates the intestinal stem cell state through CtBP2

“…When intestinal stem cells are exposed to chemically induced ER stress, consequent activation of the UPR determines their cellular fate by driving a process of differentiation while abrogating programs that drive stem cell fate. This occurs in a PERK-eIF2α-dependent manner 6 , 11 , 12 . To identify which transcription factors that drive stemness are lost in the early phase of the ER stress response, even before cells have committed to a differentiation program, we subjected LS174T colorectal cancer cells for 2 h to 400 nM of thapsigargin.…”

“…In addition to stem cell homeostasis, intervening with the UPR induces differentiation of Apc mutant adenomatous stem cells and cancer cells that maintain self-renewal capacity within tumors, which leads to suppression of tumor formation 7 , 11 , 12 . Upon deletion of intestinal Grp78 , differentiation of Apc mutant stem cells occur whilst nuclear translocation of ß-catenin remains intact 11 .…”

ER Stress and the UPR in Shaping Intestinal Tissue Homeostasis and Immunity

“…Heijmans et al showed that an activated UPR in crypt base columnar cells antagonizes stem cell properties and proliferation via stem cell-specific depletion of the ER chaperone Grp78 (87). More recently, they were able to show that heterozygosity of Grp78 in the intestinal epithelium compromises epithelial regeneration capacity and protects against adenoma formation (88). A similar mechanism to the UPR has been described in mitochondria and is termed the mitochondrial UPR (mtUPR) (89–91).…”