LIFE SCIENCES
·
2022
·
IF 6.78
Tianfeng Yang,Cheng Cheng,Rui Xu,Jian Huo,Xiujuan Peng,Yanbin Chen,Yonghong Liang,Zhiheng Su,Yanmin Zhang
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths. The WW-domain containing oxidoreductase (WWOX) protein suppresses carcinogenesis and its absence is closely related to aggressive HCC phenotypes. In this study, by using SPR analysis, cell viability assay and xenograft mice models, we found that albendazole (ABZ), a safe and effective anthelmintic drug, exhibited the binding affinity with WWOX protein and potential inhibition effect on HCC cells in vitro and in vivo . Overexpression and knockdown of WWOX confirmed that the suppression of HCC by ABZ. Flow cytometric analysis, western blotting analysis and Co-IP were conducted to study the mechanism of ABZ. Our data showed that ABZ regulated the interaction between WWOX and its binding proteins including p53 and C-MYC. Furthermore, ABZ triggered p53-induced intrinsic apoptosis and suppressed EMT-mediated migration by C-MYC/Fibronectin axis. In addition, ∆NP73 expression was significantly inhibited by ABZ, which further sensitized p53-induced intrinsic apoptosis and cell cycle arrest. In summary, ABZ could suppress the proliferation and migration of HCC cells by regulating WWOX-dependent signaling pathway.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Tianfeng Yang,Suyu Zhang,Kun Nie,Xiuhong Peng,Jian Huo,Xiao Fu,Yanmin Zhang
Although ferroptosis as an emerging way exhibits tremendous promising in the therapy of hepatocellular carcinoma (HCC), the novel therapeutic agents targeting ferroptosis are still scarce. In our previous study, we found that the natural products toosendanin (TSN) possessed significant anti-proliferative efficacy by regulating WW domain-containing oxidoreductase (WWOX) in HCC. However, there is very limited understanding about TSN-induced ferroptosis, and the role of WWOX in ferroptosis has not been studied. In present study, we investigated the effect and underlying molecular mechanisms of TSN in WWOX-mediated ferroptosis in HCC. We found that TSN induced ferroptosis in HCC cells and its effect was dependent on WWOX. RNA-seq and RT-qPCR assay identified that TSN significantly increased spermidine/spermine N1-acetyltransferase 1 (SAT1) expression while decreased solute carrier family 40 member 1 (SLC40A1) expression, which play vital roles in ferrous ion transport. Further dual-luciferase reporter assay and Co-IP assay revealed that TSN-induced WWOX activation controlled the transcriptional activity of p53 and NF-E2-related factor 2 (NRF2) by regulating their interaction. Meanwhile, IF assay and WB assay confirmed that TSN increased the nuclear distribution of p-WWOX and p-p53 dimers, but impeded the nuclear translocation of NRF2 by inducing its ubiquitination degradation, ultimately regulating the transcription of their downstream target genes. In addition, the results from cell viability assay and the tumor xenograft model verified that co-treatment of TSN, ML385 (NRF2 inhibitor), and MIRA-1 (p53 activator) could effectively inhibit HCC cells growth in the presence of Fer-1 (ferroptosis inhibitor) in vitro and in vivo. Overall, our study contributes to the necessary understanding of the molecular mechanisms of WWOX-mediated ferroptosis regulation, and identifies TSN as a potential therapeutic agent targeting ferroptosis for HCC.
研究领域:
肿瘤学
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分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2022
·
IF 10.334
Ying Zhang,Changjun Yin,Chao Wei,Shuai Xia,Zhu Qiao,Xue-Wen Zhang,Bin Yu,Jun Zhou,Rong Wang
Migration, invasion, epithelial-mesenchymal transformation (EMT), and chemotherapeutic resistance are the leading causes of therapeutic failure in people with colorectal cancer (CRC). The migration of exosomal miRNA between cancer cells and the tumor microenvironment is directly associated with malignant behavior in cancer-associated fibroblasts (CAFs). In the context of earlier research, the purpose of the current study was to assess the role and potential mechanism of miR-625-3p released by CAFs in CRC cells. Exosomes were extracted and purified from CAFs conditioned medium by ultracentrifugation. Western blot , immunohistochemistry, CCK-8, transwell assay, H&E staining, Tunnel, real-time PCR, double luciferase assay, RNA-binding protein immunoprecipitation (RIP), and immunofluorescence double staining experiments were used to investigate the effects of CAFs-Exo and miR-625-3p on CRC cell invasion, migration, proliferation, EMT, chemotherapeutic resistance, and molecular mechanisms. The current results indicated that CAFs-Exo was directly internalized by CRC cells, and exosomal miR-625-3p derived from CAFs might promote migration, invasion, EMT and chemotherapeutic resistance in CRC cells by inhibiting the CELF2/WWOX pathway, providing a potential candidate for CRC prediction and treatment.
研究领域:
肿瘤学
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分子生物学
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癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 8
·4567-4578
·
IF 5.882
Tianfeng Yang,Jian Huo,Rui Xu,Yanmin Zhang
Regorafenib (RGF), a second-line multi-kinase inhibitor in the treatment of HCC (hepatocellular carcinoma) after sorafenib failure, exposes to the risk of drug resistance and subsequent progression of HCC patients. Toosendanin (TSN), a triterpenoid has presented excellent inhibition on several tumors. The purpose of this study is to investigate the inhibitory effect of the combination of TSN and RGF on HCC cells. We identified that TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC-97L cells. The upregulation of WWOX (WW-domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC. TRC suppressed the phosphorylation of Stat3 and expression of DVL2, negatively regulated the activity of β-catenin by promoting the phosphorylation of GSK3β. In addition, the intranuclear proteins, including MMP2, MMP9, and C-MYC were significantly inhibited by TRC. The in vivo xenograft models confirmed that TRC effectually prevented the tumor growth through upregulating WWOX. Therefore, the treatment of TRC may be a potential solution of RGF resistance and promising therapeutic method in malignant HCC.
研究领域:
肿瘤学
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药理学
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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
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