iScience
·
2024
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IF 4.6
Lele Xu,Yuting Chen,Tao Wu,Jiaqi Fan,Yuying Hu,Xuefeng Gao,Yuliang Wang,Tao Chen,Xueting Zhao,Min Zeng,Fei Wang,Qingyou Zheng,Xiaojuan Pei,Dinglan Wu
Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) represent a promising novel treatment for castration-resistant prostate cancer (CRPC) with encouraging results. However, the combination targets in CRPC remain largely unexplored. N6-methyladenosine (m 6 A) has been shown to play a crucial role in cancer progression and DNA damage response. Here, we observed a higher overall level of m 6 A and a downregulation of Fat mass and obesity-associated protein (FTO), which correlated with unfavorable clinicopathological parameters in prostate cancer (PCa). Functionally, reduced FTO promotes PCa growth, while overexpression of FTO has the opposite effect. Mechanistically, FOXO3a was identified as the downstream target of FTO in PCa. FTO downregulates the expression of FOXO3a in an m 6 A-dependent manner, leading to the degradation of its mRNA. Importantly, DNA damage can degrade FTO through the ubiquitination pathway. Finally, we found that overexpression of FTO can enhance the effect of PARPi on PCa. Therefore, our findings may provide insight into novel therapeutic approaches for CRPC.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
APOPTOSIS
·
2024
·Vol. 29
·期 9
·1679-1695
·
IF 6.1
Fan Aoyu,Li Yunpeng,Zhang Yunyan,Meng Wei,Pan Wei,Chen Meixi,Ma Zhongliang,Chen Wei
Prostate cancer (PCa) is one of the most common cancers affecting the health of men worldwide. Castration-resistant prostate cancer (CRPC), the advanced and refractory phase of prostate cancer, has multiple mechanisms of resistance to androgen deprivation therapy (ADT) such as AR mutations, aberrant androgen synthase, and abnormal expression of AR-related genes. Based on the research of the AR pathway, new drugs for the treatment of CRPC have been developed in clinical practice, such as Abiraterone and enzalutamide. However, many areas in this pathway are still worth exploring. In this study, single-cell sequencing analysis was utilized to scrutinize significant genes in the androgen receptor (AR) pathway related to CRPC. Our analysis of single-cell sequencing combined with bulk-cell sequencing revealed a substantial downregulation of AR-regulated AFF3 in CRPC. Overexpression of AFF3 restricted the proliferation and migration of prostate cancer cells whilst also increasing their sensitivity towards enzalutamide, while knockdown of AFF3 had the opposite effect. To elucidate the mechanism of tumor inhibition by AFF3, we applied GSVA and GSEA to investigate the metabolic pathways related to AFF3 and revealed that AFF3 had an impact on fatty acids metabolism and ferroptosis through the regulation of ACSL4 protein expression. Based on correlation analysis and flow cytometry, we can speculate that AFF3 can impact the sensitivity of the CRPC cell lines to the ferroptosis inducer (RSL3) by regulating ACSL4. Therefore, our findings may provide new insights into the mechanisms of drug resistance in CRPC, and AFF3 may serve as a novel prognostic biomarker in prostate cancer.
研究领域:
肿瘤学
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分子生物学
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基因组学
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DOI
高影响因子
Advanced Science
·
2025
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IF 14.1
Aoyu Fan,Yunyan Zhang,Yunpeng Li,Wei Meng,Fan Wu,Wei Pan,Zhongliang Ma,Wei Chen
Prostate cancer (PCa) is one of the most common malignancies for male individuals globally. Androgen deprivation therapy (ADT) initially demonstrated significant efficacy in treating PCa; however, most cases of PCa eventually progress to castration-resistant prostate cancer (CRPC), which becomes increasingly challenging to manage. Notably, the loss or disruption of primary cilia in PCa cells may play a critical role in the progression of the disease, and there are no reports on the role of circular RNAs in ciliogenesis. Thus, this warrants further investigation.In this study, key circular RNAs linked to prostate cancer progression, and enzalutamide resistance is identified. Specifically, it is found that hsa_circ_0005185 interacts with OTUB1 and RAB8A, serving as a molecular scaffold. Hsa_circ_0005185 mediates the binding of the deubiquitinase OTUB1 to RAB8A, resulting in the deubiquitination of RAB8A. Consequently, the stable expression of RAB8A promotes the regeneration of primary cilia and enhances the production of GLI3R, an inhibitory factor in the Hedgehog signaling pathway, thereby suppressing AR activity and slowing the progression of CRPC.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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信号转导
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
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IF 4.5
Zuojie Li,Yuhao Jiang,Qing Ruan,Guangxing Yin,Peiwen Han,Xiaojiang Duan,Junbo Zhang
The specific expression of prostate-specific membrane antigen (PSMA) makes it an ideal target for the diagnosis and treatment of prostate cancer. Currently, many 99mTc-labeled PSMA-targeted tracers have been developed. However, the high renal uptake of these 99mTc-labeled tracers is a common problem that limits their clinical application. In this work, the ligand (EUKPG) using DPro-Gly as the linker was synthesized and three 99mTc-labeled complexes ([99mTc]Tc-EUKPG-EDDA, [99mTc]Tc-EUKPG-TPPTS, [99mTc]Tc-EUKPG-TPPMS) with different coligands were prepared and evaluated. Among them, [99mTc]Tc-EUKPG-EDDA showed the most favorable pharmacokinetic properties, with significantly reduced uptake in the kidney (14.04 ± 0.23% ID/g), rapid clearance and low uptake in nontarget organs, thus making it to exhibit high tumor-to-background ratios (tumor/blood: 7.47, tumor/muscle: 12.65). Affinity studies have shown that it has high specificity for PSMA both in vivo and in vitro. Therefore, [99mTc]Tc-EUKPG-EDDA has great potential as a promising molecular tracer to target PSMA for tumor imaging.
研究领域:
医学影像学
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肿瘤学
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放射化学
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DOI
PubMed
高影响因子
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
·
2025
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IF 3.3
Zhang Xiuju,Nie Xiaowei,Yu Wenxiao,Du Guanchao,Liu Shaoming,Song Yewen
MicroRNA (miRNA) has emerged as a potential diagnostic marker for malignancies, such as prostate cancer; yet, few analytical approaches have been established for the simple and effective identification and quantification of miRNA. We depict here a fluorescent dumbbell probe utilizing DNA-silver nanoclusters (DNA-AgNCs) to facilitate the simple and label-free quantification of miRNA. The fluorescent probe was methodically engineered using a double-flapped dumbbell structure, wherein the 5′ flap was synthesized using DNA-AgNCs, and the 3′ flap was extended by a G-rich sequence. The DNA scaffold rigidifies the DNA-AgNCs and the G-rich sequence, bringing them into close contact, which leads to enhanced fluorescence due to the activation of DNA-AgNCs by the G-rich sequence. Upon the introduction of miRNA, the 5′ flap of the probe unfolds, liberating the G-rich sequence from the probe, disrupting the closeness between DNA-AgNCs and the G-rich region, and resulting in decreased fluorescence. The proposed method, by incorporating target recycling and polymerase/endonuclease-assisted cycles, enables sensitive detection of miRNA with a detection limit of 4.2 fM and demonstrates high specificity for monitoring target miRNA in clinical samples, offering a robust platform for miRNA monitoring and disease diagnosis. Graphical
研究领域:
生物化学
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分子生物学
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医学诊断
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产品关联
DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-14
·
IF 6.4
Jin Shengkai,Zhou Yuhua,Lv Jing,Lu Yichen,Zhang Yuwei,Li Menglu,Feng Ninghan
Background A close relationship exists between castration-resistant prostate cancer (CRPC) and histidine metabolism by gut microbes. However, the effects of the histidine metabolite imidazole propionate (IMP) on prostate cancer (PCa) and its underlying mechanisms are not well understood.Methods We first assessed the effects of IMP on cell proliferation and migration at the cellular level. Subsequently, we investigated the mechanism of action of IMP using transcriptome sequencing, qPCR, and Western blot analysis. Finally, we validated our findings in vivo using a mouse model.Results Histidine had no effect on PCa cell proliferation; however, IMP significantly inhibited the proliferation and migration of PC3 and DU145 cells. Mechanistic studies indicate that IMP exerts its effects by upregulating PDZK1 expression, which subsequently inhibits the phosphorylation of the PI3K-AKT pathway.Conclusion sIn conclusion, IMP significantly inhibits the progression of PCa, offering new insights into potential treatments for CRPC.
研究领域:
肿瘤学
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微生物学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-17
·
IF 7
Wei Guojiang,Huang Ying,Li Wenya,Xie Yuxin,Zhang Deyi,Niu Yuanjie,Zhao Yang
Metabolic reprogramming in prostate cancer has been widely recognized as a promoter of tumor progression and treatment resistance. This study investigated its association with ferroptosis resistance in prostate cancer and explored its therapeutic potential. In this study, we identified differences in the epithelial characteristics between normal prostate tissue and tissues of various types of prostate cancer using single-cell sequencing. Through transcription factor regulatory network analysis, we focused on the candidate transcription factor, SREBF1. We identified the differences in SREBF1 transcriptional activity and its association with ferroptosis, and further verified this association using hdWGCNA. We constructed a risk score based on SREBF1 target genes associated with the biochemical recurrence of prostate cancer by combining bulk RNA analysis. Finally, we verified the effects of the SREBPs inhibitor Betulin on the treatment of prostate cancer and its chemosensitization effect. We observed characteristic differences in fatty acid and cholesterol metabolism between normal prostate tissue and prostate cancer tissue, identifying high transcriptional activity of SREBF1 in prostate cancer tissue. This indicates that SREBF1 is crucial for the metabolic reprogramming of prostate cancer, and that its mediated metabolic changes promoted ferroptosis resistance in prostate cancer in multiple ways. SREBF1 target genes are associated with biochemical recurrence of prostate cancer. Finally, our experiments verified that SREBF1 inhibitors can significantly promote an increase in ROS, the decrease in GSH, and the decrease in mitochondrial membrane potential in prostate cancer cells and confirmed their chemosensitization effect in vivo. Our findings highlighted a close association between SREBF1 and ferroptosis resistance in prostate cancer. SREBF1 significantly influences metabolic reprogramming in prostate cancer cells, leading to ferroptosis resistance. Importantly, our results demonstrated that SREBF1 inhibitors can significantly enhance the therapeutic effect and chemosensitization of prostate cancer, suggesting a promising therapeutic potential for the treatment of prostate cancer.
研究领域:
肿瘤学
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分子生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2025
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IF 14.6
Dan Feng,Jian Zhang,Huanmin Niu,Xiaoxue Zheng,Mengqi Jia,Qiqi Lu,Jing Wang,Wenxue Guo,Qi Sun,Huiqing Yuan,Hongxiang Lou
The elevated polyamines, amine-rich molecules with diverse functions in pathophysiology processes, are implicated in contributing to tumorigenesis and progression. Whether and how they affect the efficacy of chemotherapy is incompletely understood. Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe 2+ levels in vitro . Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice. Analysis of RNA-seq data indicates that heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe 2+ , is significantly upregulated in response to Spd and erastin cotreatment. Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1. Moreover, Spd and erastin significantly inhibit proteasome activity which results in a decrease in proteasomal degradation of NRF2, although many proteasome-related genes are induced either by Spd or Spd plus erastin. Thus, in addition to its pro-oncogenic activity, the supplement of Spd improves antitumor activity in combination with ferroptosis inducers and offers an optional approach to cancer treatment.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Talanta Open
·
2025
·
IF 3.7
Dong Wei,Hao Zhang,Mingyang Li,Liuxi Chu
Circulating extracellular vehicles (EVs) play a crucial role in intercellular communication by transporting a diverse array of biological signaling molecules. Growing evidence indicates that phosphoproteins within these EVs hold promise as biomarkers for diagnostic and prognostic assessments, particularly in oncology. In this study, EVtrap (extracellular vesicle total recovery and purification) was utilized to isolate urinary EVs. We then combined this with an advanced liquid chromatography-tandem mass spectrometry (LC−MS/MS) technique to perform neutral loss-information-dependent acquisition-enhanced product ion (NL-IDA-EPI) analysis. This technique is specifically tailored to quantify endogenous phosphopeptides in urinary EVs by monitoring a consistent mass loss of 49 Da (H 3 PO 4 , doubly charged state) in the MS2 spectra. In this study, over 2,000 putative phosphopeptide signals were detected in a 10-mL urine sample without the need for prior phosphopeptide enrichment, thus simplifying the process and potentially minimizing sample bias. Comparative analysis of samples from high- and low-risk prostate cancer patients and a healthy control group revealed six differentially expressed phosphopeptides. These phosphopeptides serve as a promising panel of potential biomarkers, highlighting the effectiveness of our analytical framework in tracking cancer-related signaling events via phosphorylation within EVs using NL-IDA-EPI.
研究领域:
医学
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蛋白质组学
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肿瘤学
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产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Zuojie Li,Xiaojiang Duan,Peiwen Han,Guangxing Yin,Yuhao Jiang,Qing Ruan,Junbo Zhang
The development of novel tracers targeting prostate-specific membrane antigen (PSMA) has great potential for improving the diagnosis and treatment of prostate cancer (PCa). This study aimed to improve the absolute tumor uptake and tumor-to-background ratios (TBRs) of this novel PSMA tracer by increasing the number of pharmacophores, Glu-urea-Lys (EuK), that specifically bind to PSMA. We successfully synthesized four radioligands and prepared a total of 12 stable radiotracers by coordinating 99mTc with various coligands. [99mTc]Tc-EUKD-EDDA showed the best pharmacokinetic properties both in vitro and in vivo. It effectively increased the absolute uptake in tumors and resulted in good tumor retention. Rapid clearance in nontarget organs resulted in high TBRs. High-contrast SPECT/CT images were obtained within 2–6 h after injection, suggesting that [99mTc]Tc-EUKD-EDDA has great application potential in time-lapse imaging of PCa, which is important for improving the diagnostic accuracy of PCa in clinical practice.
研究领域:
医学影像学
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核医学
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肿瘤学
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DOI
PubMed
高影响因子
CANCER LETTERS
·
2024
·
IF 9.1
Chunyu Liu,Jiawei Chen,Yukun Cong,Kang Chen,Haoran Li,Qingliu He,Liang Chen,Yarong Song,Yifei Xing
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Journal of Biomedical Nanotechnology
·
2022
·Vol. 18
·期 8
·1897-1912
·
IF 3.641
Xu Yingtian,Zhang Zhaokun,Zhang Ying,Yang Dicheng,Liang Yuan,Xu Yan
Endocrine therapy is often used for advanced prostate cancer. However, with cancer progress, prostate cancer gradually resistant to hormone which lead to serious threatens to life of patients. Herein, a multifunctional synergistic core–shell nanoplatform is reported for improving
the therapeutic effect of chemotherapy for advanced or metastatic prostate cancer, and reducing the risk of leakage of chemotherapy drugs. Particularly, Zeolitic imidazolate framework-8 (ZIF-8) is chosen as inner core to load doxorubicin, and the of liposomes which are embedded with IR780
iodide are used as outer shell, and further modified with target ligand that binds to luteinizing hormone releasing hormone receptor. The prepared nanocarrier exhibit satisfactory photothermal effect under near infrared laser irradiation, and the temperature increases to 60.8 °C within
6 min. Meanwhile, the elevated temperature accelerates the degradation of lipid shell, releasing ZIF-8 core to acidic microenvironment of tumor, and resulting in the release of doxorubicin. Moreover, in vivo and in vitro studies have shown the ZIF-D@ALIP core–shell nanoparticles
can achieve targeted drug delivery, pH and NIR dual stimuli-responsive drug release, as well as chemotherapy and photothermal therapy synergistically on the tumor site. In addition, the problem of premature leakage and changes in the physicochemical properties of anticancer drugs are avoided
under the protection of the outer shell structure. Therefore, the core–shell nanostructure proposes a new lipid membrane coating strategy to promote the effective targeting of prostate cancer cells or tissues and provides some insights in clinical treatment for advanced prostate cancer.
研究领域:
肿瘤学
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药剂学
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生物医学工程
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DOI
高影响因子
危险品化学品经营许可证（带存储）