ONCOLOGY REPORTS
·
2017
·Vol. 38
·期 6
·3583-3591
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IF 2.662
Shilei Zang,Qiling Tang,Fangrui Dong,Huan Liu,Lili Li,Fang Guo,Xuediao Pan,Haorong Lin,Weibin Zeng,Zhaoxu Cai,Qibin Zhong,Ning Zang,Linquan Zang
Curcumol, a polyphenol compound derived from the rhizome of Curcuma, has been established as an antitumor compound against multiple types of cancer, including gastric (GC), lung, liver and breast cancer. However, the molecular mechanisms undelying its anticancer activity in GC are still unclear. In this study, the antitumor efficacy of curcumol was ascertained in human gastric adenocarcinoma MGC-803 cells. An MTT assay was used to assess the viability of the MGC-803 cells treated by curcumol. The results of the Annexin V/propidium iodide (PI) staining followed by fluorescence activated cell sorting (FACS) analysis demonstrated that the cell cycle was arrested in the G2/M phase by curcumol. Annexin V-FITC/PI double staining followed by FACS analysis revealed that curcumol induced apoptosis of MGC-803 cells. FACS analysis after the cells were loaded with a DFCH-DA probe revealed that the level of reactive oxygen species (ROS) increased after the cells were treated with curcumol. In adittion, FACS analysis after the cells were loaded with JC-1 revealed that the level of mitochondrial membrane potential (MMP) decreased after the cells were treated with curcumol. Furthermore, the downregulation of isocitrate dehydrogenase 1 (IDH1) was observed in the MGC-803 cells after being treated with curcumol as determined by western blotting and RT-qPCR. In conclusion, we elucidated the antitumor effect of curcumol on MGC-803 cells and the involved mechanisms related to the induction of apoptosis, the increase of ROS, the decrease of MMP and the downregulation of IDH1.
研究领域:
肿瘤学
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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
CELL RESEARCH
·
2022
·Vol. 32
·期 7
·638-658
·
IF 46.297
Wang Xiaomin,Chen Ziqi,Xu Jun,Tang Shuai,An Nan,Jiang Lei,Zhang Yixiang,Zhang Shaoying,Zhang Qingli,Shen Yanyan,Chen Shijie,Lan Xiaojing,Wang Ting,Zhai Linhui,Cao Siyuwei,Guo Siqi,Liu Yingluo,Bi Aiwei,Chen Yuehong,Gai Xiameng,Duan Yichen,Zheng Ying,Fu Yixian,Li Yize,Yuan Liang,Tong Linjiang,Mo Kun,Wang Mingcheng,Lin Shu-Hai,Tan Minjia,Luo Cheng,Chen Yi,Liu Jia,Zhang Qiansen,Li Leping,Huang Min
Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment. In this study, we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis, conferring a therapeutic vulnerability in IDH1-mutant solid tumors. Mechanistically, SLC1A1, a Na + -dependent glutamate transporter that is preferentially expressed in endothelial cells, facilitates the influx of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria. R-2-HG hijacks SLC1A1 to promote mitochondrial Na + /Ca 2+ exchange, which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis. SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors. Moreover, we report that HH2301, a newly discovered mIDH1 inhibitor, shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models. Together, we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular endothelial cells, and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.
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
JOURNAL OF NEURO-ONCOLOGY
·
2025
·Vol. 176
·期 1
·111
·
IF 3.1
Yang Chenxuan,Wang Heda,Liu Minghang,Cai Yuang,Chi Jimei,Huang Liang,Su Meng,Wu Dongdong,Xu Bainan
Objective This study aimed to construct a perovskite quantum dot probe targeting isocitrate dehydrogenase 1 (IDH1) mutation. The probe is intended to enable rapid in vitro pathological diagnosis of IDH1-mutant glioma, guide surgeons in formulating scientific and rational resection strategies during surgery, and facilitate precise individualized intraoperative treatment for glioma patients. Methods Via surface ligand engineering, a perovskite nanocrystal (PNC) probe modified with bromobutyric acid (BBA) was developed in this study. This probe enhances water/oxygen stability and addresses the limitation that restricts the application of perovskite quantum dots as fluorescent probes. The probe was used to stain intraoperative tumor frozen sections to verify its specific recognition capability for IDH1-mutant glioma. Results Verification using 50 glioma frozen sections demonstrated that the probe could accomplish rapid pathological detection within 30 min (with a 5-minute incubation period). Fluorescence imaging showed specific green fluorescence in IDH1-mutant glioma. When compared with genetic testing results, the probe exhibited the following detection performance: sensitivity of 100%, specificity of 84%, positive predictive value of 86.2%, negative predictive value of 100%, and accuracy of 92% (κ = 0.84, P < 0.001). Conclusions This BBA-stabilized perovskite probe enables rapid and specific in vitro detection of IDH1-mutant glioma. It provides real-time guidance for glioma surgery, is expected to assist surgeons in achieving precise resection of glioma, and thus advances the development of precision neuro-oncology.
研究领域:
神经肿瘤学
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纳米医学
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分子诊断
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生物医学成像
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CANCER RESEARCH
·
2026
·
IF 16.6
Zhao Yuheng,Ou Chunxian,Huang Huimin,Wang Yujue,Shen Jiaxi,Li Yaoyi,He Qingmei,Han Zeteng,Xie Yuer,Zhong Tianyun,Xu Sha,Liu Na,Wang Gao-Yuan,Ma Jun,Li Yingqin
Metabolic reprogramming under therapeutic stress may represent a targetable vulnerability for cancer treatment. Elucidation of the metabolic alterations linked to chemotherapy in nasopharyngeal carcinoma (NPC) could uncover potential therapeutic strategies. Using proteomics and transcriptomic profiles, we identified wild-type IDH1 as a crucial metabolic enzyme upregulated in gemcitabine plus cisplatin chemotherapy (GP)-resistant NPC. IDH1 reprogrammed nucleotide metabolism in response to chemotherapy, linking DNA damage repair (DDR) to ferroptosis resistance via DHODH, thereby contributing to chemoresistance in NPC. Mechanistically, α-ketoglutarate (α-KG), a metabolite of IDH1, enhanced chromatin accessibility to promote DHODH transcription via α-KG-dependent dioxygenase ALKBH5-recruited HNRNPC. The DHODH inhibitor BAY2402234 markedly sensitized NPC cells to chemotherapy. Clinically, a prognostic model based on DDR and ferroptosis signatures effectively predicted disease relapse risk post-chemotherapy in NPC. This study links DDR to ferroptosis defense via the IDH1/α-KG/ALKBH5/DHODH axis, suggesting DHODH inhibition as a promising therapeutic strategy to overcome chemoresistance in tumors harboring wild-type IDH1.
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Youwei Wang,Yang Yang,Xiaowei Cao,Zhensheng Liu,Bing Chen,Qiu Du,Xiaoxia Lu
Purpose Circulating tumor DNA (ctDNA) is more representative and accurate than biopsy and is also conducive to dynamic monitoring, facilitating accurate diagnosis and prognosis of glioma. Therefore, the present study aimed to establish and validate a novel amplified method for the detection of IDH1 R132H and BRAF V600E, which were associated with the genetic diagnosis of glioma.Patients and Methods A dual-signal amplification method based on magnetic aggregation and catalytic hairpin assembly (CHA) was constructed for the simultaneous detection of ctDNAs. When target ctDNAs are present, the CHA reaction is initiated and leads to the assembly of Au-Ag nanoshuttles (Au-Ag NSs) onto magnetic beads (MBs). Further enrichment of MBs under an external magnetic field facilitated the dual-signal amplification of SERS.Results The limit of detection (LOD) for IDH1 R132H and BRAF V600E in serum was as low as 6.01 aM and 5.48 aM. The reproducibility and selectivity of the proposed SERS analysis platform was satisfactory. Finally, the platform was applied to quantify IDH1 R132H and BRAF V600E in the serum of subcutaneous-tumor‑bearing nude mice, and the results obtained by SERS were consistent with those from quantitative real-time polymerase chain reaction (qRT-PCR).Conclusion The present study showed that the dual-signal amplification method is a simple and ultrasensitive strategy for gliomas-associated ctDNAs detection, which is crucial for early diagnosis and dynamic monitoring.
研究领域:
肿瘤学
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分子诊断
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生物医学工程
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分析化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yuangui Tang,Chenyun Dai,Huihui Yang,Xian Yang,Ziyu Chen,Jinxiu Dou,Liuxu Zhang,Tao Bai,Junfang Zheng
Non-histone proteins localized in membrane, cytosol and nucleus are lactylated to promote tumor progression. However, whether mitochondrial proteins undergo lactylation and contribute to tumor progression remains unexplored. Here, we identified multiple lactylated mitochondrial proteins in human renal cell carcinoma (RCC) cells using lactylome profiling. Among these, malate dehydrogenase 2 (MDH2)–the only lactylated protein in the tricarboxylic acid (TCA) cycle–emerged as a key target, with K239 as its lactylation site. MDH2 K239la levels are regulated by KAT8 and SIRT3. Under low-glucose, high-lactate conditions mimicking the tumor microenvironment, MDH2 K239la elevated the NADH/NAD + ratio to drive ATP production and boosted NADPH generation to reduce ROS. This enables cells to alleviate oxidative stress, sustain mitochondrial function, and promote RCC malignancy in vitro and in vivo . Mechanistically, MDH2 K239la enhances MDH2 enzymatic activity and strengthens its interaction with the citrate transporter SLC25A1. This facilitates citrate efflux, fueling IDH1-dependent NADPH production when lactate serves as an energy source. Collectively, we unveil a lactylation-dependent mechanism that reprograms mitochondrial metabolism to confer oxidative stress resistance and drive RCC progression. Targeting mitochondrial proteins lactylation, exemplified by MDH2 K239la , represents a promising therapeutic strategy for RCC.
研究领域:
癌症生物学
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生物化学
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细胞生物学
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分子生物学
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代谢工程
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肿瘤学
✓ 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）