β-Arrestin1 inhibits chemotherapy-induced intestinal stem cell apoptosis and mucositis

Zhan, Yashi; Xu, Chenyu; Liu, Z; Yang, Yanling; Tan, Siwei; Jiang, Jie; Liu, Huiling; Chen, J; Wu, Bin

doi:10.1038/cddis.2016.136

Cited by 36 publications

(38 citation statements)

References 47 publications

(59 reference statements)

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“…These findings are consistent with previous observations that 5-FU induces gastrointestinal mucositis. 47 We also confirmed the increase in HMGB1 in small intestine tissues following 5-FU treatment and the protective effects of NecroX-7 against gastrointestinal mucosal injury by effectively inhibiting HMGB1 release ( Supplementary Figures 3, 4). This finding implies that HMGB1 acts as a mechanism similar to OM pathogenesis and can be a key mediator in GI mucositis.…”

Section: Discussionsupporting

confidence: 74%

Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis

Nam

Kim

et al. 2019

Mucosal Immunology

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Oral mucositis (OM) is a common complication in cancer patients undergoing anticancer treatment. Despite the clinical and economic consequences of OM, there are no drugs available for its fundamental control. Here we show that high-mobility group box 1 (HMGB1), a "danger signal" that acts as a potent innate immune mediator, plays a critical role in the pathogenesis of OM. In addition, we investigated treatment of OM through HMGB1 blockade using NecroX-7 (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxothiomorpholin-4-yl)methyl-1Hindole-7-yl]amine). NecroX-7 ameliorated basal layer epithelial cell death and ulcer size in OM induced by chemotherapy or radiotherapy. This protective effect of NecroX-7 was mediated by inhibition of HMGB1 release and downregulation of mitochondrial oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and macrophage inflammatory protein (MIP)-1β, as well as the expression of p53upregulated modulator of apoptosis (PUMA) and the excessive inflammatory microenvironment, including nuclear factor-kB (NF-kB) pathways. In conclusion, our findings suggest that HMGB1 plays a key role in the pathogenesis of OM; therefore, blockade of HMGB1 by NecroX-7 may be a novel therapeutic strategy for OM.

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Section: Discussionsupporting

confidence: 74%

Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis

Nam

Kim

et al. 2019

Mucosal Immunology

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“…Kwon, 2016). Attenuation of apoptosis in these organs can preserve stem cells, leading to improving organ tolerance and attenuation of side effects (Zhan et al, 2016). Some studies have been conducted to investigate the protective effect of curcumin on chemotherapy-induced toxicity in normal tissues.…”

Section: Curcumin Attenuates Chemotherapy-induced Apoptosis In Normmentioning

confidence: 99%

Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy

Mortezaee

Salehi

Mirtavoos-Mahyari

et al. 2019

Journal Cellular Physiology

256

154

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Cancer incidences are growing and cause millions of deaths worldwide. Cancer therapy is one of the most important challenges in medicine. Improving therapeutic outcomes from cancer therapy is necessary for increasing patients’ survival and quality of life. Adjuvant therapy using various types of antibodies or immunomodulatory agents has suggested modulating tumor response. Resistance to apoptosis is the main reason for radioresistance and chemoresistance of most of the cancers, and also one of the pivotal targets for improving cancer therapy is the modulation of apoptosis signaling pathways. Apoptosis can be induced by intrinsic or extrinsic pathways via stimulation of several targets, such as membrane receptors of tumor necrosis factor‐α and transforming growth factor‐β, and also mitochondria. Curcumin is a naturally derived agent that induces apoptosis in a variety of different tumor cell lines. Curcumin also activates redox reactions within cells inducing reactive oxygen species (ROS) production that leads to the upregulation of apoptosis receptors on the tumor cell membrane. Curcumin can also upregulate the expression and activity of p53 that inhibits tumor cell proliferation and increases apoptosis. Furthermore, curcumin has a potent inhibitory effect on the activity of NF‐κB and COX‐2, which are involved in the overexpression of antiapoptosis genes such as Bcl‐2. It can also attenuate the regulation of antiapoptosis PI3K signaling and increase the expression of MAPKs to induce endogenous production of ROS. In this paper, we aimed to review the molecular mechanisms of curcumin‐induced apoptosis in cancer cells. This action of curcumin could be applicable for use as an adjuvant in combination with other modalities of cancer therapy including radiotherapy and chemotherapy.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Kallifatidis

Smith

Morera

et al. 2019

Molecular Cancer Therapeutics

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b-Arrestins are classic attenuators of G-protein-coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that b-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. b-Arrestin-1 (ARRB1) and b-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n ¼ 63 and 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated. The consequence of forced expression of ARRBs on tumor growth and response to Gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared with normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, diseasespecific-mortality, and failure to Gemcitabine þ Cisplatin (GþC) chemotherapy; $80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity toward Gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. CRISPR-Cas9-mediated gene-knockout of ARRB1 resulted in the reversal of this aggressive phenotype. ARRBs regulate cancer stem cell-like properties in bladder cancer and are potential prognostic indicators for tumor progression and chemotherapy response.

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β-Arrestin1 inhibits chemotherapy-induced intestinal stem cell apoptosis and mucositis

Cited by 36 publications

References 47 publications

Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis

Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis

Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy

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

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