Nutrients
·
2022
·Vol. 14
·期 15
·3042
·
IF 6.706
Jun Chen,Zhiguang Duan,Yannan Liu,Rongzhan Fu,Chenhui Zhu
The metastasis of esophageal squamous cell carcinoma (ESCC) is a leading cause of death worldwide, however, it has a poor prognosis. Ginsenoside Rh4 is a rare saponin that has been shown to have potential antitumor effectiveness in ESCC. However, the utility of Rh4 in ESCC metastasis and its undiscovered mode of action has not yet been explored. In this study, we found that Rh4 could inhibit ESCC metastasis by regulating the Wnt/β-catenin signaling pathway and the level of c-Myc, which is an important transcription factor in cancer. In in vitro experiments, Rh4 could inhibit the migration and invasion of ESCC cells without affecting cell viability. In in vivo experiments, Rh4 restrained ESCC metastasis to the lymph nodes and lungs via the suppression of epithelial-mesenchymal transition (EMT). The Wnt agonist HLY78 promoted EMT and migration of ESCC cells, whereas treatment of Rh4 can attenuate the promotion effect of HLY78. The siRNA knocking out c-Myc can also significantly reduce the expression of EMT-related marker proteins. This study illustrates a new concept for further research on the mechanism of Rh4 in ESCC.Keywords:metastasis;ginsenoside Rh4;ESCC;Wnt/β-catenin;c-Myc
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2023
·
IF 4
Hang-fei Chen,Zhang-ping Li,Qi Wu,Chun Yu,Jing-Yi Yan,Yong-feng Bai,Sheng-mei Zhu,Mao-xiang Qian,Ming Liu,Li-feng Xu,Zheng Peng,Feng Zhang
Hyperactivation of ribosome biosynthesis (RiBi) is a hallmark of cancer, and targeting ribosome biogenesis has emerged as a potential therapeutic strategy. The depletion of TAF1B , a major component of selectivity factor 1 ( SL1 ), disrupts the pre-initiation complex, preventing RNA polymerase I from binding ribosomal DNA and inhibiting the hyperactivation of RiBi. Here, we investigate the role of TAF1B , in regulating RiBi and proliferation in stomach adenocarcinoma (STAD). We disclosed that the overexpression of TAF1B correlates with poor prognosis in STAD, and found that knocking down TAF1B effectively inhibits STAD cell proliferation and survival in vitro and in vivo. TAF1B knockdown may also induce nucleolar stress, and promote c-MYC degradation in STAD cells. Furthermore, we demonstrate that TAF1B depletion impairs rRNA gene transcription and processing, leading to reduced ribosome biogenesis. Collectively, our findings suggest that TAF1B may serve as a potential therapeutic target for STAD and highlight the importance of RiBi in cancer progression.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2025
·
IF 12
Di Wang,Xiao-ya Wang,Wen-jing Li,Cheng-hui Liang,Yu-xin Zou,Jin-wei Xiao,Qing-mei Kang,Jun-han Wang,Ling Mao,Jun-jie Chen,Xue-jia Zhai,Ji-tao Zhuang,Xian-Yan Yang,Hong-ying Jiang,Tian-hua Shen,Jie Liu,Qian Wen,Jiang-jie Duan,Jun Wang,Shi-cang Yu
The oncoprotein c-Myc is a prominent target in cancer therapy and modulating its stability is a promising potential treatment strategy. Phosphorylation at Ser62 is the primary mechanism by which c-Myc degradation is suppressed, which extends its half-life. Consequently, identifying kinases that regulate the phosphorylation of c-Myc at Ser62 may pave the way for novel intervention strategies. In this study, we revealed that acetaldehyde dehydrogenase 18A1 (ALDH18A1), a key enzyme in glutamate-proline metabolism, acts as a protein kinase through its γ-glutamate kinase (γ-GK) domain, which mediates the phosphorylation of the Ser62 site of c-Myc and suppresses its degradation. In turn, stabilized c-Myc directly increases the transcription of ALDH18A1 . This positive feedback loop sustains the mutual high expression of both proteins, which promotes the development of various tumors. Thonzonium bromide (TB), a small-molecule inhibitor screened from a Food and Drug Administration-approved drug library, was found to block ALDH18A1-mediated phosphorylation of c-Myc at Ser62 and attenuate tumor progression in preclinical models. Overall, these findings reveal the therapeutic potential of inhibiting the ALDH18A1 - MYC regulatory circuit in human cancers.
研究领域:
肿瘤学
·
分子生物学
·
信号转导
·
癌基因调控
·
代谢酶功能
·
蛋白质稳定性
·
靶向治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Haofan Hu,Shangwu Ning,Furong Liu,Ze Zhang,Weifeng Zeng,Yachong Liu,Zhibin Liao,Hongwei Zhang,Zhanguo Zhang
Hepatocellular carcinoma (HCC) with MYC oncogene amplification remains a serious challenge in clinical practice. Recent advances in comprehensive treatment strategies, particularly the combination of radiotherapy and immunotherapy, offer new hope. To further improve efficacy while lowering radiation doses, nanopharmaceuticals based on high-Z elements have been extensively studied in radio-immunotherapy. In this work, a hafnium-based metal–organic framework (Hf-MOF), UiO-66-Hf(2OH)-CB-839/BSO@HA (UiO-66-Hf(2OH)-C/B@HA), was designed to codeliver telaglenastat (CB-839) and buthionine sulfoximine (BSO), which synergistically inhibited glutamine metabolism and alleviated tumor hypoxia. Further modification with hyaluronic acid (HA) enhanced tumor targeting, ultimately strengthening the efficacy of radiotherapy in MYC-amplified HCC. Beyond increasing reactive oxygen species (ROS) generation, promoting DNA damage, and inducing tumor apoptosis, more importantly, UiO66-Hf(2OH)-C/B@HA triggered immunogenic cell death (ICD), driving the antitumor immune response. Combination with immune checkpoint blockade (ICB) further enhanced the efficacy, accompanied by increased infiltration of T cells with high granzyme B expression (GZMB+ T cells) within the tumor microenvironment (TME). In the orthotopic HCC model, established with MYC-amplified tumor cells, intravenous administration of UiO66-Hf(2OH)-C/B@HA significantly potentiated the efficacy of radio-immunotherapy, resulting in superior tumor regression. In summary, our study provides insights into the design of Hf-MOF for radio-immunotherapy and proposes a promising therapeutic approach for MYC-amplified HCC.
研究领域:
肿瘤学
·
药剂学
·
放射生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANTICANCER RESEARCH
·
2024
·Vol. 44
·期 7
·2861-2870
·
IF 1.6
YINA ZHANG,XIAOCEN NIU,YUANHE WANG,SHUTING BAO,PEIYUE JIANG,XIAORUI DONG
Background/Aim: Glutamine metabolism is crucial in cell proliferation, aging, and apoptosis across various cancer types. Existing research indicates that Sirtuin 4 (SIRT4), primarily located in mitochondria, modulates this process. This study aimed to clarify the regulatory relationship between SIRT4 and glutamine metabolism in cervical cancer. Materials and Methods: SIRT4 mRNA levels and their clinical correlation to cervical cancer were analyzed using the UALCAN database. Immunohistochemistry (IHC) was performed to assess SIRT4 protein expression in tissue samples from cervical cancer patients. Transient transfection was employed to create Hela and Siha cell lines with overexpressed SIRT4, mitogen-activated extracellular signal-regulated kinase (MEK), and glutaminase 1 (GLS1). The impact on cellular functions was studied using MTT, soft agar, transwell, and western blotting assays. Glutamate and ATP levels were also measured to evaluate metabolic changes. Results: Low levels of SIRT4 mRNA in cervical cancer tissues correlated with tumor metastasis and poor survival rates. Overexpression of SIRT4 led to suppressed cell proliferation, colony growth, and motility, along with significant down-regulation of GLS expression, a key contributor to glutamine metabolism. Additionally, SIRT4 overexpression resulted in the inactivation of the MEK/ERK/c-myc signaling pathway, while overexpression of MEK reversed these effects. Notably, the inhibitory effects of SIRT4 on cell proliferation, colony formation, migration, and invasion in Hela and Siha cells were significantly attenuated following GLS1 overexpression. Conclusion: SIRT4 acts as an anti-cancer agent in cervical cancer by inhibiting glutamine metabolism through the MEK/ERK/c-myc signaling pathway, providing a novel sight for cervical cancer therapy.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
癌症代谢
✓ 已验证
DOI
PubMed
高影响因子
Cancer Communications
·
2023
·Vol. 43
·期 3
·338-364
·
IF 16.2
Peng Xia,Hao Zhang,Haofeng Lu,Kequan Xu,Xiang Jiang,Yuke Jiang,Xiangdong Gongye,Zhang Chen,Jie Liu,Xi Chen,Weijie Ma,Zhonglin Zhang,Yufeng Yuan
Background Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6-adenosine (METTL5) controls the development of HCC and the Warburg effect. Methods In the current study, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione-S-transferase pulldown, coimmunoprecipitation, RNA sequencing, non-targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. Results We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A ( LDHA ), enolase 1 ( ENO1 ), triosephosphate isomerase 1 ( TPI1 ), solute carrier family 2 member 1 ( SLC2A1 ), and pyruvate kinase M2 ( PKM2 ). The c-Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c-Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient-derived tumor xenograft (PDX) models, adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice. Conclusions These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
生物化学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Qiang Zhang,Kaisa Cui,Yue Kong,Jing Yu,Zhanhao Luo,Xiaoya Yang,Liang Gong,Yanchun Xie,Jiuxiu Lin,Chen Liu,Zongjin Zhang,Yugeng Liu,Bingxin Liu,Dayi Liang,Wanyi Zeng,Zhen He,Ping Lan
c-Myc (Myc)-driven cancers exhibit aggressive phenotypes and therapeutic resistance. Here, integrating CRISPR-Cas9 screening, we identify dihydroorotate dehydrogenase (DHODH) as a promising target in Myc-driven cancer. Mechanistically, DHODH interacts with Myc to stabilize it independently of its enzymatic activity, thereby antagonizing SKP2-mediated polyubiquitination and proteasomal degradation. EN4, a Myc transcriptional activity inhibitor, disrupts DHODH-Myc interaction, promoting Myc degradation via SKP2. Additionally, Myc transcriptionally activates DHODH, enhancing pyrimidine biosynthesis and ferroptosis defense, processes dependent on DHODH enzymatic activity. Clinically, DHODH positively correlates with Myc, activating pyrimidine metabolism and ferroptosis defense in Myc-driven cancers. Hyperactivation of the DHODH-Myc axis is linked to colorectal cancer progression and poor prognosis. Therapeutically, combining EN4 with a DHODH enzymatic inhibitor demonstrates potent antitumor efficacy in Myc-driven colorectal cancer. Overall, our findings elucidate the metabolic and non-metabolic roles of DHODH in Myc-driven cancer, underscoring its dual potential as a therapeutic target addressing both enzymatic and non-enzymatic functions.
研究领域:
肿瘤学
·
分子生物学
·
癌症遗传学
·
代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Xueqing Zhou,Xuan Liu,Xiqin Yang,Li Wang,Yiling Hong,Keke Lian,Guoxi Qiu,Xuwei Shang,Zhongjun Ma,Hong Yuan,Fuqiang Hu
Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) play an important role in the development of tumors by secreting a variety of cytokines or directly communicating with tumor cells, making TAMs-targeted therapeutic strategies very attractive. It has been reported that oncogene c-Myc is related to every aspect of the oncogenic process of tumor cells and the alternative activation of macrophages. Hence, we constructed a glycolipid nanocarrier containing ROS-responsive peroxalate linkages (CSOPOSA) for ROS-triggered release of drugs and further modified it with Ex 26 (Ex 26-CSOPOSA), a selective sphingosine 1-phosphate receptor 1 (S1PR1) antagonist, to achieve the dual-targeted delivery of the c-Myc inhibitor JQ1 via S1PR1, which is overexpressed on both tumor cells and TAMs, thereby inducing apoptosis of tumor cells, and blocking M2 polarization of macrophages. More strikingly, our studies found that JQ1 could effectively inhibit the migration of tumor cells induced by M2 macrophages-derived exosomes via blocking Caveolin-1 related intercellular exosome exchange through lncRNA H19 and miR-107. The in vivo results revealed that this dual-targeted delivery strategy effectively inhibited tumor growth and metastasis with less systemic toxicity, providing a potential method for effective tumor treatment.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
纳米技术
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2024
·
IF 4.7
Lan Liang,Chenming He,Xue Han,Jia Liu,Liuhong Yang,Fengjiao Chang,Yami Zhang,Jie Lin
Background Precancerous lesions of gastric cancer (PLGC) represent critical stages in gastric cancer progression, with a high risk of malignancy. Current treatments, such as Helicobacter pylori eradication, show limited efficacy in reversing precancerous molecular changes. Zuojin Pill (ZJP), a traditional Chinese medicine, has demonstrated potential for treating digestive disorders and may offer a promising approach for PLGC intervention.Objective This study aims to investigate the therapeutic effects and mechanisms of ZJP in treating PLGC, focusing on its active components, target pathways, and molecular interactions. By using advanced analytical techniques, we provide a scientific foundation for ZJP’s potential application in early gastric cancer intervention.Methods Using ultra-high performance liquid chromatography-quadrupole orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap HRMS), we identified active components in ZJP. A network pharmacology approach was then applied to construct a “ZJP-compound-target-disease” network. Molecular docking and molecular dynamics simulations were conducted to analyze the stability and interactions of the main active components of ZJP with core protein targets in PLGC. Animal experiments were used to validate significant targets and pathways in vivo.Results Tangeritin, Isorhamnetin, Caffeic Acid, Azelaic Acid, and Adenosine were identified as the main active components of ZJP in the treatment of PLGC, with key targets including PIK3R1, MAPK3, SRC, JAK2, STAT3, and PIK3CA. Molecular docking and molecular dynamics simulations further confirmed the relationship between compounds and target proteins. The potential molecular mechanism of ZJP predicted by network pharmacology analysis was confirmed in PLGC rats. ZJP downregulated IL-6, TNF-α, c-myc, p-MEK1 and p-ERK1/2, effectively reversing the progression of PLGC.Conclusion ZJP can reverse MNNG-induced PLGC, potentially through inhibition of the MEK/ERK/c-myc pathway and regulation of cellular proliferation and apoptosis.
研究领域:
中药学
·
肿瘤学
·
生物信息学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Huizhen Tian,Qigang Pan,Jianfeng Wu,Juanjuan Liao,Yuwei Wan,Ke Pei,Qiong Liu,Lingbing Zeng,Yanli Cao,Qiaofa shi,Nanzhen Kuang,LiJuan Sun,Xiaomin Yu,Xiaotian Huang
Background Coxsackievirus B3 (CVB3) is a leading cause of viral myocarditis and is currently lacking specific pharmacological treatments, highlighting the critical need for therapeutic development. Icariin (ICA), a prenylated flavonol glycoside, was previously found to exhibit several pharmacological effects, but its potential to combat CVB3 remains uninvestigated. Purpose This study aimed to elucidate the anti-CVB3 efficacy of ICA and elucidate its molecular mechanisms. Methods CVB3-infected HeLa cells, H9C2 cells and neonate rat ventricular cardiomyocytes (NRVCs) were selected as in vitro models, and were treated with ICA at 1 and 10 μM. Additionally, BALB/c mice that were infected with CVB3 via intraperitoneal injection were chosen as in vivo model and were treated with ICA or ribavirin over 3 days. The effect of ICA against CVB3 was determined by Cell Counting Kit-8 (CCK-8) assay, western blot, real-time fluorescence quantitative PCR (RT–qPCR), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) and flow cytometry. Results In this study, it was found that ICA is capable of reducing CVB3 viral load both in vitro and in vivo . Mechanistic studies suggested that ICA prevents cardiomyocyte apoptosis by attenuating the S100 calcium binding protein A6 (S100A6)/β-catenin/c-Myc signaling pathway. Additionally, ICA inhibits the secretion of proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and CXC motif chemokine ligand 2 (CXCL2) in heart tissue, thereby mitigating CVB3-induced myocarditis. Moreover, ICA also regulates the immune response of CD4 + T, CD8 + T and Treg cells by changing the cells numbers in spleen tissue. Lastly, ICA can reduce the load of other enteroviruses (such as CVA6, CVA16 and EV71) in rhabdomyosarcoma (RD) cells as well. Conclusion Our findings indicate that ICA provides significant protection against CVB3 infection by modulating the S100A6/β-catenin/c-Myc signaling pathway, suggesting its potential use as a novel drug against CVB3 infection in clinical application.
研究领域:
药理学
·
病毒学
·
心脏病学
·
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Epigenomics
·
2022
·
IF 4.357
Hanlin Li,Yanjie Yang,Jianpeng Yu,Boya Zhang,Xuanrong Chen,Shimiao Zhu,Yuanjie Niu,Zhiqun Shang
Aims: We aimed to determine whether intronic circRNA acts as a molecular sponge in castration-resistant prostate cancer (CRPC). Materials & methods: A gene chip technique was used to conduct sequencing. A qPCR experiment was performed to verify the result. Radioimmunoprecipitation, RNA pull-down and dual-luciferase reporter assays were performed to particularly expound its function. Verification of downstream effects was carried out through qPCR and western blot, and a xenograft assay was performed in vivo for verification. Results: Intronic circRNA hsa_circ_0092339 in the nucleus was highly expressed in CRPC cell lines. hsa_circ_0092339 did not regulate the expression of its parental gene. hsa_circ_0092339 functions like a molecular sponge, preventing degradation of C-MYC mRNA by absorbing hsa-mir-940. Conclusion: hsa_circ_0092339 plays a critical role in CRPC through targeting C-MYC indirectly by absorbing hsa-mir-940.Plain language summaryOur research breaks the mold by investigating a novel function of RNA and a novel regulatory mechanism. Our research provides a new therapeutic target for prostate cancer treatment and broadens the understanding of prostate cancer.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
·
前列腺癌
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2024
·Vol. 191
·期 2
·1-12
·
IF 5.3
Wang Xiaoying,Yuan Wei,Kuang Yijing,Chen Xuyuan,Wang Xiaoning,Zhang Xiaoyu
A ratiometric electrochemical immunosensor is proposed for simultaneous detection of cellular-myelocytomatosis oncoprotein (C-myc) and B-cell lymphoma 2 (Bcl-2) via the potential-resolved strategy. It relied on multi-role co-loaded alloy composites (CLACs) and poly(3,4-ethylenedioxythiophene) (PEDOT)-graphene oxide (GO)-multiwalled carbon nanotubes (MWCNTs) (PGM) modified electrodes. CLACs with good catalytic and enzyme-like properties were synthesized in one step by loading tetramethylbenzidine (TMB) or methylene blue (MB) into Pt-Pd alloy and used as label materials. After immunological reactions, CLACs showed distinguishable dual differential pulse voltammetry signals at − 0.26 V and 0.38 V, corresponding to C-myc and Bcl-2, and the PGM had an electrochemical signal at 1.2 V, which could be used as a reference signal to construct a ratiometric sensor. CLACs had a satisfactory synergistic effect with the PGM, and eventually achieved quadruple signal amplification. Thus, benefiting from multiple magnification and ratiometric self-calibration functions, sensitive detections of C-myc and Bcl-2 were achieved, with detection limits as low as 0.5 and 2.5 pg mL −1 , respectively. Additionally, when the designed method was applied to blood samples from lymphoma patients, results consistent with the ELISA kit were obtained. This will open avenues for constructing multiple protein detection sensors. Graphical abstract
研究领域:
生物分析化学
·
电化学
·
生物传感器
·
癌症诊断
·
纳米材料
·
免疫传感
·
分析化学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）