Cell Death & Disease
·
2025
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IF 9.6
Huang Hongli,Chai Yihan,Wu Xuewei,Wang Sen,Li Binglin,Wang Yanyan,Zheng Wen,Wu Yuefeng,Meng Di,Wang Hua,Tu Zhengliang,Du Chengli,Lyu Xiayi,Li Guiying,Guo Wei
Non-genetic resistance of cancer remains poorly understood in clinical research and practice. To better understand resistant cancer cell heterogeneity, we isolated a novel riboflavin + NOTCH1 + population from cisplatin-naïve and -resistant lung cancer cell lines and patient specimens with or without immunotherapy and chemotherapy. This population was also identified as SLC52A2 (one of the riboflavin transporters) + NOTCH1 + cells in single-cell RNA sequencing (scRNA-seq) data derived from advanced lung tumors before therapy. Despite its therapy-naïve origin, the population, designated as stably resistant cancer cells (SRCC), exhibited the epithelial state, innate and stable resistance to therapy (chemotherapy, targeted therapy and immunotherapy), cell dormancy, elevated reactive oxygen species (ROS), and anti-apoptotic and anti-ferroptotic survival. These cellular and molecular characteristics distinguished SRCC from other resistant populations, including cancer stem-like cells (CSC), epithelial-mesenchymal transition (EMT) cells, and drug-tolerant persisters (DTP). The non-canonical NOTCH1 pathway, but not the inactivated canonical NOTCH1 pathway, played a critical role in the resistance of SRCC. Specifically, it modulates cell cycle, iron metabolism, EMT, and ferroptosis vulnerability in SRCC at the transcriptional level. It also controls the initiation of ferroptosis in lysosomes via a posttranslational NOTCH1-AKT-BAX axis. Inhibition of the non-canonical NOTCH1 pathway re-sensitizes these dormant and resistant cells to cisplatin-induced cell death in vitro and in vivo, including ferroptosis, apoptosis, and necroptosis. Our study contributes to a deeper understanding of cancer resistance and promotes the development of more effective therapeutic strategies against resistant cancer cells.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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细胞信号转导
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药物耐药性
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铁死亡研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2018
·
IF 4.936
Liming Yu,Zhi Li,Xue Dong,Xiaodong Xue,Yu Liu,Shu Xu,Jian Zhang,Jinsong Han,Yang Yang,Huishan Wang
Diabetes exacerbates oxidative/nitrative stress during myocardial ischemia-reperfusion (MI/R) injury. Recent studies highlighted the cardioprotective actions of polydatin. However, its effect on diabetic MI/R injury and the underlying mechanisms remain unknown. This work was undertaken to evaluate the effect of polydatin on diabetic MI/R injury with a focus on Notch1/Hes1 signaling and myocardial oxidative/nitrative stress. Streptozotocin- (STZ-) induced diabetic rats were administered with polydatin (20 mg/kg/d) in the absence or presence of DAPT (a γ-secretase inhibitor) or LY294002 (a PI3K/Akt inhibitor) and then subjected to MI/R injury. Polydatin administration preserved cardiac function and reduced myocardial infarct size. Moreover, polydatin ameliorated myocardial oxidative/nitrative stress damage as evidenced by decreased myocardial superoxide generation, malondialdehyde, gp91phox expression, iNOS expression, NO metabolite level, and nitrotyrosine content and increased eNOS phosphorylation. However, these effects were blocked by DAPT administration. DAPT also inhibited the stimulatory effect of polydatin on the Notch1/Hes1-Pten/Akt signaling pathway in a diabetic myocardium. Additionally, LY294002 not only abolished polydatin’s antiapoptotic effect but also reversed its inhibitory effect on myocardial oxidative/nitrative stress. Polydatin effectively reduced MI/R injury and improved left ventricular functional recovery under diabetic condition by ameliorating oxidative/nitrative stress damage. Importantly, Notch1/Hes1-mediated activation of Pten/Akt signaling played a crucial role in this process.
研究领域:
心脏病学
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药理学
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分子生物学
·
糖尿病研究
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2025
·Vol. 44
·期 1
·1-31
·
IF 12.8
Chang Chunxiao,Wang Meng,Li Jia,Qi Sihao,Yu Xiaojuan,Xu Jun,Shi Shengbin
Background Chronic liver injury is a key factor in diseases like hepatocellular carcinoma (HCC), steatohepatitis (NASH), and viral hepatitis type B and C (HBV, HCV). Understanding its molecular mechanisms is crucial for effective treatment. The NOTCH1 signaling pathway, though not fully understood, is implicated in liver injury and may be a potential therapeutic target.Methods Clinical HCC, HBV, HCV and NASH samples and additional in vitro and in vivo performances were subjected to confirm the role of NOTCH1 and its downstream targets via a series of biochemical assays, molecular analysis approaches and targeted signaling pathway assay, etc.Results The present study first verified the abnormal elevation of NOTCH1 in hepatocytes from patients with steatohepatitis, HCC, HBV, HCV, and mouse models. Crucially, we discovered that hepatocyte-specific NOTCH1 knockout reduces hepatocellular damage in chronic liver inflammation and HCC mouse models, whereas adeno-associated virus serotype 8 (AAV8)-mediated NOTCH1 overexpression in hepatocytes exacerbates liver injury-related phenotype on-setting. Mechanistically, we showed that NOTCH1 has a new role in controlling ferroptosis and oxidative damage in hepatocytes. It interacts with Kelch-like ECH-associated protein 1 (KEAP1) and is directly recruited through its intracellular domain (NICD1). Additionally, the KEAP1 recruited by NOTCH1 impeded the binding stability of KEAP1-NFE2 like BZIP transcription factor 2 (Nrf2), promote the separation of KEAP1 and Nrf2, thereby reducing the stability of Nrf2 and hindering the ubiquitination-related proteasome degradation of Nrf2. Crucially, we also discovered that NOTCH1’s ANK domain is essential for NICD1-KEAP1 contacts and signaling activation. The inability of NOTCH1 with ANK domain mutants (ΔANK) to connect with KEAP1 and increase its expression emphasizes the importance of the ANK domain in KEAP1-NRF2 signaling. By reversing the downregulation of KEAP1 and the overexpression of NRF2, ANK function is linked to ferroptosis and ROS buildup. ANK domain targeting may slow the course of HCC and liver damage.Conclusion sTargeting the NOTCH1-KEAP1-NRF2 axis as a possible chronic hepatic injury therapy is supported by these findings, which identify NOTCH1-KEAP1 as an NRF2 suppressor that accelerates the progression of liver injury.
研究领域:
分子生物学
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生物化学
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癌症生物学
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肝病学
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信号转导
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遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2022
·
IF 2.65
Haijun Gao,Yan Zhang,Xiaojin Mo,Lele Huo,Yanping Luo,Ting Zhang,Xingming Ma,Wei Hu,Tao Jing
Background. Liver cancer, particularly hepatocellular carcinoma (HCC), is the fourth leading cause of cancer-related death worldwide. Sorafenib is a crucial drug for the treatment of advanced HCC, but it is difficult to meet the challenge of increasing clinical demands due to its severe side effects and drug resistance. Hence, development of novel antitumor drugs is urged. Previous studies showed that pseudolaric acid B (PAB) could reduce the expression of protein kinase B (PKB/Akt), a downstream effector of Notch signaling, facilitating cell apoptosis in HCC. The disruption of Notch signaling was verified to exacerbate malignant progression and drug resistance, however, the antitumor effect of PAB on Notch signaling in HCC remains unclear. Thus, this study aims to investigate the anti-HCC effect of PAB in association with the regulation of Notch1/Akt signaling. Methods. CCK-8 assay and transwell assay were used to examine the cell proliferation and invasion in Huh7 cells after treatment with PAB and a Notch inhibitor DAPT. Moreover, the cell cycle of Huh7 cells after treatment with PAB was analyzed using flow cytometry. Finally, the changes of Notch1, Jagged1, Hes1, and Akt expression at the protein and mRNA level in Notch1/Akt signaling in Huh7 cells after treatment with PAB and DAPT were analyzed using immunofluorescence assay and real-time qPCR. Results. The proliferation rate of Huh7 cells exposed to PAB of 0.5, 1, 2, 4, 8, 10, 20, 40, 80, 100, and 200 μmol/L revealed a time-and dose-dependent decrease in vitro, showing cell cycle arrest at G2/M phase . Furthermore, compared with the untreated group, at the concentration of 40 μmol/L, the proliferation rate and invasion rate of Huh7 cells in PAB, DAPT, and PAB-DAPT combination (PAB + DAPT) group were significantly decreased , but the PAB + DAPT showed no synergistic antiproliferation and anti-invasion effect in comparison with PAB treatment alone . In addition, compared with the untreated group, PAB and DAPT alone significantly downregulated the expression of Notch1, Jagged1, Hes1, Akt mRNA, or/and protein in Huh7 cells , but there was no significant difference in synergistic downregulated effect between the PAB + DAPT group and the PAB group . Conclusion. PAB can suppress proliferation and invasion of HCC cells through downregulating the expression of Notch1/Akt signaling protein and mRNA, and may be a potential novel antitumor drug candidate for the clinical treatment of HCC in the future.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
·
2022
·
IF 5.702
Yang Xiao-bo,Zu Heng-bing,Zhao Yong-fei,Yao Kai
Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and a selective 5-hydroxytryptamine 2C receptor antagonist, is widely applied in treating depression and insomnia symptoms in several neurogenerative diseases. However, the neuroprotective effect of agomelatine in Alzheimer’s disease (AD) is less known. In this study, a total of 30 mice were randomly divided into three groups, namely, wild type (WT), APP/PS1, and agomelatine (50 mg/kg). After 30 days, the Morris water maze was performed to test the cognitive ability of mice. Then, all mice were sacrificed, and the hippocampus tissues were collected for ELISA, Western blot, and immunofluorescence analysis. In this study, we found that agomelatine attenuated spatial memory deficit, amyloid-β (Aβ) deposition, tau phosphorylation, and neuroinflammation in the hippocampus of APP/PS1 mice. Further study demonstrated that agomelatine treatment upregulated the protein expression of DHCR24 and downregulated P-Akt, P-mTOR, p-p70s6k, Hes1, and Notch1 expression. In summary, our results identified that agomelatine could improve cognitive impairment and ameliorate AD-like pathology in APP/PS1 mice via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Agomelatine may become a promising drug candidate in the therapy of AD.
研究领域:
神经科学
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药理学
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神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Protein & Cell
·
2024
·
IF 13.6
Ma Wei,Zhang Lu,Chen Weilong,Chang Zhaoxia,Tu Juchuanli,Qin Yuanyuan,Yao Yuwen,Dong Mengxue,Ding Jiajun,Li Siqin,Li Fengkai,Deng Qiaodan,Yang Yifei,Feng Tingting,Zhang Fanrong,Shao Xiying,He Xueyan,Zhang Lixing,Hu Guohong,Liu Quentin,Jiang Yi-Zhou,Zhu Shu,Xiao Zhi,Su Dan,Liu Tong,Liu Suling
Tumor-resident microbiota in breast cancer promote cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increases the chemosensitivity of breast cancer by impairing BCSCs.
研究领域:
肿瘤学
·
微生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2020
·
IF 3.347
Xiaolei Wang,Kaiyan Lou,Xiaodong Song,Huijuan Ma,Xinyi Zhou,Huan Xu,Wei Wang
Mebendazole (MBZ) is a tubulin-suppressive antihelmintic agent with low toxicity, which has been repurposed to treat different types of tumors. Chemoresistance is quite common in refractory or relapsed T cell acute lymphoblastic leukemia (T-ALL), which leads to dismal chances of recovery. In this study, MBZ was found to suppress the proliferation and reduce the viability of T-ALL cell line, CCRF-CEM, and its chemoresistant derivative, CEM/C1, at nanomolar concentrations. The inhibitive effects were found to be dose-dependent and not to be affected by the chemoresistance of CEM/C1 cells. Cell cycle arrest, caspase 3/7 activation and tubulin disruption were found in the MBZ-treated T-ALL cells. Notch1 signaling, which is often aberrantly activated in T-ALL cells, was showed to be suppressed by MBZ treatments. MBZ administration in murine T-ALL models also suppressed the growth of CEM/C1 cells, indicating that MBZ may be developed as a therapeutic agent for chemoresistant T-ALLs. The mRNA levels of the Notch1 and Hes1 were also confirmed to be suppressed by MBZ in vivo, which was consistent with the in vitro observations. This study demonstrated, for the first time, that MBZ could inhibit chemoresistant T-ALL cells both in vitro and in vivo , and the Notch1 signaling pathway was suppressed by MBZ treatment.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
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