iScience
·
2025
·
IF 4.1
Shuyuan Chang,Ayaka Tomii,Yunfei Zhou,Xun Yang,Yihong Dong,Jun Yan,Aodi Wu,Yumeng Wang,Qingxin Zhang,Hongxue Meng,Lei Yu,Wei Sun,Dabin Liu
Succinate is a crucial metabolite in the TCA cycle and contributes to cancer development. However, the role of exogenous succinate in hepatocellular carcinoma (HCC) is unclear. Here, we report that the concentration of succinate in HCC tissues is lower compared to adjacent normal tissues, as determined by spatial metabolomics and quantitative metabolomics analysis. Succinate supplementation exhibits an anti-tumorigenic effect, inhibiting cell proliferation and colony formation in liver cancer cells but not in non-tumor LO2 cells. Additionally, succinate supplementation significantly reduces tumor formation in xenograft nude mice models and carcinogen-induced WT mice models. The anti-tumorigenic function of succinate is mechanistically mediated by FN1-activated SQLE-related cholesterol biosynthesis. Our study demonstrates that exogenous succinate acts as a cholesterol biosynthesis inhibitor to suppress HCC both in vitro and in vivo , highlighting its potential therapeutic applications.
研究领域:
肿瘤学
·
代谢组学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Xiaolin Zhang,Zhen Dong,Yuanmiao Yang,Chaolong Liu,Jisheng Li,Wenli Sun,Yikang Zhu,Yang Shen,Zhi Wang,Muhan Lü,Hongjuan Cui
The incidence rate of colorectal cancer (CRC) has been increasing significantly in recent years, and it is urgent to develop novel drugs that have more effects for its treatment. It has been reported that many molecules extracted from the root bark of Morus alba L. (also known as Cortex Mori) have antitumor activities. In our study, we identified morusinol as a promising anticancer agent by selecting from 30 molecules extracted from Morus alba L. We found that morusinol treatment suppressed cell proliferation and promoted apoptosis of CRC cells in vitro. Besides this, we observed that morusinol induced cytoprotective autophagy. The GO analysis of differentially expressed genes from RNA-seq data showed that morusinol affected cholesterol metabolism. Then we found that key enzyme genes in the cholesterol biosynthesis pathway as well as the sterol regulatory element binding transcription factor 2 (SREBF2) were significantly downregulated. Furthermore, additional cholesterol treatment reversed the anti-CRC effect of morusinol. Interestingly, we also found that morusinol treatment could promote forkhead box O3 (FOXO3a) nuclear accumulation, which subsequently suppressed SREBF2 transcription. Then SREBF2-controlled cholesterol biosynthesis was blocked, resulting in the suppression of cell proliferation, promotion of apoptosis, and production of autophagy. The experiments in animal models also showed that morusinol significantly impeded tumor growth in mice models. Our results suggested that morusinol may be used as a candidate anticancer drug for the treatment of CRC.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Xuan Jiang,Manli Wang,Guoliang Cui,Yuanyuan Wu,Zhonghong Wei,Suyun Yu,Aiyun Wang,Wei Zou,Yanhong Pan,Xiaoman Li,Yin Lu
Background Tetramethylpyrazine (TMP), a key bioactive constituent derived from Ligusticum wallichii Franchat , has demonstrated efficacy in mitigating multidrug resistance (MDR) in human breast cancer (BC) cells. However, the precise mechanisms underlying its action remain poorly understood. Purpose Cancer stem cells (CSCs) are widely recognized as the primary contributors to MDR. This investigation seeks to elucidate the role and mechanisms through which TMP counteracts MDR by attenuating CSC-like characteristics. Methods Various assays, including flow cytometry, sphere formation, and Western blotting, were employed to evaluate TMP's effects on breast cancer stem cell (BCSC)-like phenotypes in vitro. In vivo , extreme limiting dilution assays and immunohistochemistry (IHC) were executed to assess the impacts of TMP on BCSC frequency and the levels of stemness markers. Mechanistically, RNA sequencing was performed to uncover the key biological processes involved in TMP's effects on BCSCs. Further experiments, encompassing micro scale thermophoresis (MST), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and amino acid mutation analyses, were utilized to identify the essential targets and corresponding binding sites of TMP. Finally, the effects of TMP on BCSC-like phenotypes were confirmed using cells with mutated amino acid residues, which allowed us to investigate the specificity of TMP's binding sites. To further evaluate the impact of TMP on drug resistance, doxorubicin-resistant MCF7 (MCF-7 ADR ) cells, along with corresponding cell lines harboring mutated amino acid residues, were employed. Results TMP was found to inhibit BCSC-like properties both in vitro and in vivo , evidenced by a reduction in the CD44 + /CD24 - population, sphere formation capability, and expression of stemness markers. Mechanistic studies revealed that TMP targets 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. TMP binds to Asp-767 of HMGCR, thereby inhibiting its activity and reducing cholesterol synthesis. The influence of TMP on BCSC-like phenotypes was nullified by overexpression of wild-type HMGCR, while mutations in the binding site of HMGCR had no effect on TMP's inhibition of BCSC-like properties. Additionally, TMP mitigated MDR by targeting HMGCR. Conclusion These findings suggest that TMP alleviates MDR by reducing BCSC-like traits through targeting HMGCR and disruption of cholesterol biosynthesis in BC. This provides new insights into the mechanisms through which TMP alleviates MDR and offers new lead compound for exploring HMCGR antagonists.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Qian Hu,Mengyao Wang,Meng Chen,Jinjin Wang,Ting Niu
Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma, with two-thirds of patients relapsing or resisting existing therapies, highlighting the urgent need for effective treatments. Toosendanin (TSN), a triterpenoid from Meliae Cortex, exhibits significant anti-cancer activity by modulating cell survival and proliferation. This study investigates the anti-lymphoma effects and underlying mechanisms of TSN, proposing it as a potential therapeutic agent to address the challenges of DLBCL. Network pharmacology, molecular docking, and transcriptome sequencing were employed to predict TSN's anti-DLBCL potential. Findings were validated through in vitro and in vivo experiments, including cell viability assays, flow cytometry, quantitative PCR, Western blotting, reverse experiments with small-molecule inhibitors or genetic editing, and a cell-derived xenograft (CDX) model. Bioinformatics analyses revealed TSN's strong binding affinity to PI3Kα/β and Polo-like kinase 1 (PLK1). Experiments showed that TSN downregulated the PI3K/Akt signaling pathway and reduced PLK1 mRNA and protein levels, inducing apoptosis, cell cycle arrest, and cell death in DLBCL cells. RNA sequencing and metabolic assays indicated TSN upregulated cholesterol biosynthesis in DLBCL cells. Co-treatment with a statin enhanced TSN's anti-DLBCL effects while mitigating hepatic and pulmonary toxicity. This study identifies TSN as a dual inhibitor of PI3K and PLK1 with significant therapeutic potential for DLBCL. It also proposes a lipid-modulating strategy to enhance TSN's cytotoxicity while reducing adverse effects, offering a promising approach to improve DLBCL treatment outcomes.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
生物信息学
✓ 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）