β-Arrestin-2 modulates radiation-induced intestinal crypt progenitor/stem cell injury

Abstract

Intestinal crypt progenitor/stem (ICPS) cell apoptosis and vascular endothelial cell apoptosis are responsible for the initiation and development of ionizing radiation (IR)-evoked gastrointestinal syndrome. The signaling mechanisms underlying IR-induced ICPS cell apoptosis remain largely unclear. Our findings provide evidence that β-arrestin-2 (βarr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. βArr2-deficient mice exhibited decreased ICPS cell and intestinal Lgr5+ (leucine-rich repeat-containing G-protein-coupled receptor 5-positive) stem cell apoptosis, promoted crypt proliferation and reproduction, and protracted survival following lethal doses of radiation. Radioprotection in the ICPS cells isolated from βarr2-deficient mice depended on prolonged nuclear factor-κB (NF-κB) activation via direct interaction of βarr2 with IκBα and subsequent inhibition of p53-upregulated modulator of apoptosis (PUMA)-mediated mitochondrial dysfunction. Unexpectedly, βarr2 deficiency had little effect on IR-induced intestinal vascular endothelial cell apoptosis in mice. Consistently, βarr2 knockdown also provided significant radioresistance by manipulating NF-κB/PUMA signaling in Lgr5+ cells in vitro. Collectively, these observations show that targeting the βarr2/NF-κB/PUMA novel pathway is a potential radiomitigator for limiting the damaging effect of radiotherapy on the gastrointestinal system. Significance statement: acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiotherapy. The issue of whether the critical factor for the initiation of radiation-induced intestinal injury is intestinal stem cell apoptosis or endothelial cell apoptosis remains unresolved. βArrs have recently been found to be multifunctional adaptor of apoptosis. Here, we found that β-arrestin-2 (βarr2) deficiency was associated with decreased radiation-induced ICPS cell apoptosis, which prolonged survival in abdominally irradiated mice. Moreover, βarr2 deficiency-mediated intestinal progenitor/stem cell radioprotection relied on protracted NF-κB activation and subsequent suppression of PUMA induction. Our results suggest that ICPS cell apoptosis is the factor involved in the initiation and development of radiation-induced gastrointestinal syndrome. βArr2 is a potential target for lessening radiation-induced ICPS cell apoptosis.

β‐Arrestin1‐mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation

“…3C). The previous studies have shown that the number of surviving crypts following radiation was positively correlated with the number of ISCs (7,20). Therefore, we quantitatively analyzed ISC variation in response to radiation using Lgr5-GFP mice.…”

“…Inhibition of ER stress may compromise the beneficial effects of barr1 deficiency on crypt regeneration in response to radiation IR has been shown to activate ER stress in IECs (20,21). To explore the role of ER stress in the barr1 deficiency-mediated increase in crypt regeneration after radiation, we applied the chemical agent salubrinal, a known ER stress inhibitor.…”

β-Arrestins Regulate Stem Cell-Like Phenotype and Response to Chemotherapy in Bladder Cancer

“…ARRB1 promotes stemness in non-small cell lung cancers, where it acts downstream of nicotinic acetylcholine receptors (18), as well as in leukemia-initiating cells where it promotes self-renewal (19). Furthermore, although ARRB1 inhibits apoptosis in intestinal stem cells induced by chemotherapy (20), ARRB2 may, under certain circumstances (e.g., ionizing radiation), promote apoptosis of intestinal crypt progenitor/stem cells (21). The role of ARRBs in bladder cancer has not yet been reported.…”

β‑arrestin2 promotes 5‑FU‑induced apoptosis via the NF‑κB pathway in colorectal cancer

“…Nonetheless, the expression and clinicopathological significance of β-arrestin2 in CRC have not been reported. Liu et al (17) demonstrated that β-arrestin2 deficiency protracts the activation of the NF-κB pathway and suppresses radiation-induced intestinal crypt progenitor cell apoptosis (17). However, the role of β-arrestin2 β-arrestin2 promotes 5-FU-induced apoptosis via the NF-κB pathway in colorectal cancer in chemo-induced colon epithelial cell apoptosis remains to be explored.…”