Nature Communications
·
2023
·Vol. 14
·期 1
·1-20
·
IF 16.6
Yan Hao,Wu Wentong,Hu Yuhuai,Li Jinjin,Xu Jiangxin,Chen Xueqin,Xu Zhifei,Yang Xiaochun,Yang Bo,He Qiaojun,Luo Peihua
The hepatotoxicity of regorafenib is one of the most noteworthy concerns for patients, however the mechanism is poorly understood. Hence, there is a lack of effective intervention strategies. Here, by comparing the target with sorafenib, we show that regorafenib-induced liver injury is mainly due to its nontherapeutic target Eph receptor A2 (EphA2). EphA2 deficiency attenuated liver damage and cell apoptosis under regorafenib treatment in male mice. Mechanistically, regorafenib inhibits EphA2 Ser897 phosphorylation and reduces ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) by affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis. Meanwhile, we found that schisandrin C, which can upregulate the phosphorylation of EphA2 at Ser897 also has protective effect against the toxicity in vivo. Collectively, our findings identify the inhibition of EphA2 Ser897 phosphorylation as a key cause of regorafenib-induced hepatotoxicity, and chemical activation of EphA2 Ser897 represents a potential therapeutic strategy to prevent regorafenib-induced hepatotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2024
·
IF 3.4
Xu Bo,Liu Ning,Zhou Taicheng,Chen Jian,Jiang Liyu,Wu Wentong,Fu Huangxi,Chen Xueqin,Yan Hao,Yang Xiaochun,Luo Peihua,Yang Bo,Xu Zhifei,He Qiaojun
Regorafenib, an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases, has been approved for the treatment of metastatic colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma by the US Food and Drug Administration and European Medicines Agency. However, regorafenib-induced cardiotoxicity increases the risk of mortality. Despite reports that regorafenib can cause mitochondrial dysfunction in cardiomyocytes, the molecular mechanism of regorafenib-induced cardiotoxicity is much less known and there is an urgent need for intervention strategies. Here, we treated mice with vehicle or 200 mg/kg regorafenib daily for 42 days by gavage or treated cardiomyocyte lines with 8, 16 or 32 μM regorafenib, and we found that regorafenib could cause apoptosis, mitochondrial injury and DNA damage in cardiomyocytes. Mechanistically, regorafenib can reduce the expression of EPHA2, which inhibits AKT signaling, leading to cardiomyocyte apoptosis and cardiotoxicity. In addition, we showed that recovering EPHA2 expression via plasmid-induced overexpression of EPHA2 or schisandrin C, a natural product, could prevent regorafenib-induced cardiotoxicity. These findings demonstrated that regorafenib causes cardiomyocyte apoptosis and cardiac injury by reducing the expression of EPHA2 and schisandrin C could prevent regorafenib-induced cardiotoxicity by recovering EPHA2 expression, which provides a potential management strategy for regorafenib-induced cardiotoxicity and will benefit the safe application of regorafenib in clinic.
研究领域:
肿瘤学
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心脏病学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Biomed Research International
·
2021
·
IF 3.411
Fengqin Wang,Hanzhong Zhang,Zhigang Cheng
EPHA2 is a member of the ephrin receptor tyrosine kinase family and is closely related to the malignant tumor progression. The effect of EPHA2 on OSCC is not clear. This study explored the role of EPHA2 and AKT/mTOR signaling pathways in Cal-27 cell invasion and migration. The expression of EPHA2 and EPHA4 in human OSCC and normal oral tissue was detected by immunohistochemistry. EPHA2-overexpressing and EPHA2-knockdown Cal-27 cells were established, and the cells were treated with an AKT inhibitor (MK2206) and mTOR inhibitor (RAD001). The expression of EPHA2 was detected by qRT-PCR, cell proliferation was evaluated by MTT assay, cell migration and invasion were examined by scratch and Transwell assay, and cell morphology and apoptosis were assessed by Hoechst 33258 staining. Western blot was performed to detect the expression of proteins related to AKT/mTOR signaling, cell cycle, and pseudopod invasion. EPHA2 and EPHA4 were highly expressed in clinical human OSCC. Overexpression of EPHA2 promoted the proliferation, migration, and invasion of Cal-27 cells, inhibited cell cycle blockage and apoptosis, and enhanced the activity of the AKT/mTOR signaling pathway. MK2206 (AKT inhibitor) and RAD001 (mTOR inhibitor) reversed the effect of EPHA2 overexpression on the biological behavior of Cal-27 cells. EPHA2 promotes the invasion and migration of Cal-27 human OSCC cells by enhancing the AKT/mTOR signaling pathway.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2015
·Vol. 52
·期 2
·228-234
·
IF 1.145
Gao Aichao,Wang Xichao,Yu Haiyan,Li Na,Hou Yubo,Yu Weixian
Porphyromonas gingivali s ( Pg ) as the major pathogenic bacterium of chronic periodontitis can cause alveolar bone resorption. Lipopolysaccharide (LPS) is its main virulence factor. The Eph family plays an important role in maintaining bone homeostasis. In this study, the effects of P. gingivalis lipopolysaccharide ( Pg -LPS) on the expression of EphA2 in osteoblasts and osteoclasts were investigated. MC3T3-E1 cells and RAW264.7 cells were separately cultured in osteoblast-conditioned medium and osteoclast-conditioned medium to induce their differentiation into osteoblasts and osteoclasts, respectively. MC3T3-E1 cells were treated with 1 μg/mL of Pg -LPS 3, 7, and 14 d later, while RAW264.7 cells were treated with 10 μg/mL of Pg -LPS 1, 3, and 5 d later. The results have shown that Pg -LPS increased the expression of EphA2 both in osteoblasts and osteoclasts, decreased the expression of osteogenic-related genes ( ALP , Sp7 ), and increased the expression of osteoclast-related genes ( MMP9 , c-fos , ACP5 , CtsK , and NFATc1 ). Tartrate-resistant acid phosphatase (TRAP) staining illustrated that Pg -LPS promoted osteoclast differentiation and decreased the activity of alkaline phosphatase. Therefore, analysis indicates that, when treated with Pg -LPS, the expression of EphA2 is upregulated while the activity of osteoblasts and osteoclasts was reduced and increased, respectively. Our data suggest that EphA2 is closely related to the formation of osteoblasts and resorption of osteoclast and is likely to play an role in bone resorption induced in chronic periodontitis. These findings may provide information on new targets for prevention and treatment of chronic periodontitis.
研究领域:
牙医学
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免疫学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Oncotarget
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2016
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IF 5.008
Jianwen Zhao,Fengfeng Zhao,Xiyong Wang,Xiaobo Fan,Guoqiu Wu
A novel multifunctional nano-drug delivery system based on reversal of peptide charge was successfully developed for anticancer drug delivery and imaging. Mesoporous silica nano-particles (MSN) ~50 nm in diameter were chosen as the drug reservoirs, and their surfaces were modified with HIV-1 transactivator peptide-fluorescein isothiocyanate (TAT-FITC) and YSA-BHQ1. The short TAT peptide labeled with FITC was used to facilitate intranuclear delivery, while the YSA peptide tagged with the BHQ1 quencher group was used to specifically bind to the tumor EphA2 membrane receptor. Citraconic anhydride (Cit) was used to invert the charge of the TAT peptide in neutral or weak alkaline conditions so that the positively charged YSA peptide could combine with the TAT peptide through electrostatic attraction. The FITC fluorescence was quenched by the spatial approach of BHQ1 after the two peptides bound to each other. However, the Cit-amino bond was unstable in the acidic atmosphere, so the positive charge of the TAT peptide was restored and the positively charged YSA moiety was repelled. The FITC fluorescence was recovered after the YSA-BHQ1 moiety was removed, and the TAT peptide led the nano-particles into the nucleolus. This nano-drug delivery system was stable at physiological pH, rapidly released the drug in acidic buffer, and was easily taken up by MCF-7 cells. Compared with free doxorubicin hydrochloride at an equal concentration, this modified MSN loaded with doxorubicin molecules had an equivalent inhibitory effect on MCF-7 cells. This nano-drug delivery system is thus a promising method for simultaneous cancer diagnosis and therapy.
研究领域:
纳米技术
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药学
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癌症研究
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Thoracic Cancer
·
2020
·Vol. 11
·期 6
·1476-1486
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IF 2.61
Kun Zheng,Runze Chen,Yanxue Sun,Zhenquan Tan,Ye Liu,Xiao Cheng,Junke Leng,Zhaoming Guo,Pengcheng Xu
Background Although photodynamic therapy (PDT) has emerged as a potential alternative to conventional chemotherapy, the low reactive oxygen species (ROS) yield of the photosensitizer such as TiO 2 nanoparticles has limited its application. In addition, it is difficult to achieve effective tumor treatment with a single tumor therapy. Methods We used TiOx nanocomposite (YSA-PEG-TiO X ) instead of TiO 2 as a photosensitizer to solve the problem of insufficient ROS generation in PDT. Benefiting from the desired mesoporous structure of TiOx, Cantharidin (CTD), one of the active components of mylabris, is loaded into TiOx for targeted combination of chemotherapy and PDT. The cellular uptake in human non-small cell lung carcinoma cell line (A549) and human normal breast cell line (MCF 10A) was evaluated by confocal microscopy. in vitro cytotoxicity was evaluated using Cell Counting Kit-8 assay. The ROS was detected via a chemical probe DCFH-DA and the photodynamic treatment effect of YSA-PEG-TiOx was further evaluated by a living-dead staining. The cell apoptosis was detected by the flow cytometry. Results Our findings showed that the modification of YSA peptide improved the cytotoxicity of YSA-PEG-TiO X /CTD to EphA2 overexpressing A549 non-small cell lung cancer (NSCLC) than non-YSA modified counterparts. In addition, TiOx generated adequate ROS under X-ray irradiation to further kill cancer cells. Flow analysis results also proved the superiority of this combined treatment. Conclusions YSA-PEG-TiO X nanoparticles could significantly increase ROS production under X-ray exposure and provide a new drug delivery nanocarrier for CTD in combination with PDT to achieve effective NSCLC treatment.
研究领域:
纳米技术
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癌症研究
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治疗学
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）