Tegaserod maleate exerts anti-tumor effects on prostate cancer via repressing sonic hedgehog signaling pathway DOI Creative Commons

Maoping Cai,

Shengdong Ge, Yaying Hong

et al.

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 29, 2025

Abstract Prostate cancer (PCa) is a highly common type of malignancy and affects millions men in the world since it easy to recur or emerge therapy resistance. Therefore, urgent find novel treatments for PCa patients. In current study, we found that tegaserod maleate (TM), an FDA-approved agent, inhibited proliferation, colony formation, migration as well invasion, caused arrest cell cycle, promoted apoptosis cells vitro. addition, TM suppressed tumor growth cell-derived xenograft (CDX) mouse model vivo. Mechanistically, exerted anti-tumor effects via downregulating GLI2, its downtream targets, thus inhibiting sonic hedgehog (SHH) signaling pathway. brief, our findings demonstrated effectively activities by suppressing SHH pathway provided potential new agent treatment PCa.

Language: Английский

Inhibition of phosphoglycerate dehydrogenase induces ferroptosis and overcomes enzalutamide resistance in castration-resistant prostate cancer cells DOI Creative Commons
Jinxiang Wang, Leli Zeng,

Nisha Wu

et al.

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 70, P. 100985 - 100985

Published: June 15, 2023

Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in first step of serine synthesis pathway (SSP), is overexpressed multiple types cancers. The androgen receptor inhibitor enzalutamide (Enza) primary therapeutic drug for patients with castration-resistant prostate cancer (CRPC). However, most eventually develop resistance to Enza. association SSP Enza remains unclear. In this study, we found that high expression PHGDH was associated CRPC cells. Moreover, increased led ferroptosis by maintaining redox homeostasis Enza-resistant Knockdown caused significant GSH reduction, induced lipid peroxides (LipROS) increase and cell death, resulting inhibiting growth cells sensitizing treatment both vitro vivo. We also overexpression promoted Furthermore, pharmacological inhibition NCT-503 effectively inhibited growth, ferroptosis, overcame Mechanically, triggered decreasing GSH/GSSG levels increasing LipROS production as well suppressing SLC7A11 through activation p53 signaling pathway. stimulating inducers (FINs) or synergistically sensitized enzalutamide. synergistic effects were verified a xenograft nude mouse model. combination restricted xenografts Overall, our study highlights essential roles mediating CRPC. Therefore, inducer targeted could be potential strategy overcoming

Language: Английский

Citations

49
Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer DOI Creative Commons
Wenhao Wang, Tiewen Li,

Zhiwen Xie

et al.

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 14, 2024

Abstract Background Cancer-associated fibroblasts (CAFs) are heterogeneous and can influence the progression of prostate cancer in multiple ways; however, their capacity to present process antigens PRAD has not been investigated. In this study, antigen presentation process-related CAFs (APPCAFs) were identified using bioinformatics, clinical implications APPCAF-related signatures Methods SMART technology was used sequence transcriptome primary isolated from patients undergoing different treatments. Differential expression gene (DEG) screening conducted. A CD4 + T-cell early activation assay assess degree T cells. The datasets obtained Cancer Genome Atlas (TCGA) database NCBI Gene Expression Omnibus (GEO), list 431 genes InnateDB database. Subsequently, APP-related by nonnegative matrix factorization (NMF) based on a single-cell seq (scRNA) matrix. GSVA functional enrichment analyses performed depict biological functions. risk signature (APPCAFRS) developed least absolute shrinkage selection operator (LASSO) regression analysis, independence score as prognostic factor evaluated univariate multivariate Cox analyses. Furthermore, biochemical recurrence-free survival (BCRFS)-related nomogram established, immune-related characteristics assessed ssGSEA function. immune treatment response further analyzed Tumor Immune Dysfunction Exclusion (TIDE) tool. levels hub APPCAFRS verified cell models. Results There 134 upregulated 147 downregulated genes, totaling 281 differentially expressed among CAFs. functions pathways DEGs significantly enriched processing processes, MHC class II protein complex transport vesicle, binding, intestinal network for IgA production. Androgen withdrawal diminished effect NMF clustering APPRGs, pseudotime analysis yielded CAF subtype CTSK MRC2 CAF-C1. CAF-C1 cells exhibited ligand‒receptor connections with epithelial Additionally, we found strong association between inflammatory Through differential NoneAPP-CAF-C2 subgroups, 55 significant identified, namely, APPCAFRGs. Based profiles APPCAFRGs, divided TCGA-PRAD cohort into two clusters consistent cluster genetic coefficient serving evaluation index. Four THBS2, DPT, COL5A1, MARCKS, develop capable predicting BCR occurrence patients. stability accuracy constructed Gleason grade (p = n.s.), PSA < 0.001), stage 0.05), 0.01). infiltration showed positive correlation abundance resting memory cells, M1 macrophages, dendritic score. addition, mRNA MARCKS models results bioinformatics analysis. Conclusions four potential APPCAFRGs developed, interaction microenvironment may play crucial role castration resistance PRAD. This novel approach provides valuable insights pathogenesis offers unexplored targets future research.

Language: Английский

Citations

16
Cancer plasticity in therapy resistance: Mechanisms and novel strategies DOI

Xing Niu,

Wenjing Liu,

Zhang Yinling

et al.

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 76, P. 101114 - 101114

Published: June 22, 2024

Language: Английский

Citations

16
Lactoferrin conjugated radicicol nanoparticles enhanced drug delivery and cytotoxicity in prostate cancer cells DOI

Zeinab Kooshan,

Srilakshmi Srinivasan, Taskeen Iqbal Janjua

et al.

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177300 - 177300

Published: Jan. 1, 2025

Language: Английский

Citations

3
A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer DOI Creative Commons

Xiannan Meng,

Qingxuan Wu,

Chengsong Cao

et al.

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 23, 2025

The sustained activation of androgen receptor splice variant-7 (AR-V7) is a key factor in the resistance castration-resistant prostate cancer (CRPC) to second-generation anti-androgens such as enzalutamide (ENZ). AR/AR-V7 protein regulated by E3 ubiquitin ligase STUB1 and complex involving HSP70, but precise mechanism remains unclear. High-throughput RNA sequencing was used identify differentially expressed circular RNAs (circRNAs) ENZ-resistant control CRPC cells. coding potential circSRCAP confirmed polysome profiling LC–MS. function validated vitro vivo using gain- loss-of-function assays. Mechanistic insights were obtained through immunoprecipitation analyses. A novel circRNA, circSRCAP, identified shown be upregulated C4-2B (ENZR-C4-2B) cells, correlating with increased AR-V7 levels. generated via splicing eIF4A3, forming loop structure exported from nucleus helicase DDX39A. Mechanistically, encodes 75-amino acid peptide (circSRCAP-75aa) that inhibits ubiquitination AR/AR-V7's co-chaperone HSP70 disrupting interaction STUB1. This process results upregulation expression promotes ENZ Xenograft tumor models further role progression its therapeutic target for CRPC. provides an epigenetic influencing stability offers promising treating

Language: Английский

Citations

2
AZGP1P2/UBA1/RBM15 Cascade Mediates the Fate Determinations of Prostate Cancer Stem Cells and Promotes Therapeutic Effect of Docetaxel in Castration-Resistant Prostate Cancer via TPM1 m6A Modification DOI Creative Commons
Hong Wang, Liu Ji, Xiaojun Zhu

et al.

Research, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

Prostate cancer (PCa) is a common malignant tumor with high morbidity and mortality worldwide. The prostate stem cell (PCSC) model provides novel insights into the pathogenesis of PCa its therapeutic response. However, roles molecular mechanisms specific genes in mediating fate decisions PCSCs carcinogenesis remain to be elusive. In this study, we have explored expression, function, mechanism AZGP1P2, pseudogene AZGP1, regulating stemness apoptosis treatment resistance docetaxel castration-resistant (CRPC). We revealed that AZGP1P2 was downregulated CRPC lines PCSCs, while it positively associated progression-free interval. Upregulation enhanced sensitivity CRPCs via inhibiting their stemness. RNA pull-down mass spectrometry analysis, co-immunoprecipitation assay, immunoprecipitation assay demonstrated could bind UBA1 RBM15 as "writer" methyltransferase form compound. UBA1, an E1 ubiquitin-activating enzyme, contributed protein degradation ubiquitination modification. Methylated displayed controlled mRNA decay TPM1 m6A methylation. Furthermore, xenograft mouse patient-derived organoids showed effect increased by vivo. Collectively, these results imply mediates promotes suppressing growth metastasis UBA1/RBM15-mediated CRPC.

Language: Английский

Citations

33
Prostate Cancer: A Journey Through Its History and Recent Developments DOI Open Access

Hamza Mallah,

Zania Diabasana,

Sina Soultani

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(2), P. 194 - 194

Published: Jan. 9, 2025

Prostate cancer is one of the most common diseases among men worldwide and continues to pose a serious threat health. This review shows history new developments in management prostate cancer, with an emphasis on range therapeutic approaches, such as hormone therapy, radiation surgery, innovative targeted therapeutics. The evolution these treatments examined light clinical outcomes, patient quality life, emerging resistance mechanisms, recently shown vitamin D-based strategies. New that have potential increase survival rates reduce side effects are also discussed, including PARP inhibitors (PARPis), immunotherapy, tailored medication. Additionally, use biomarkers sophisticated imaging methods decision-making explored, focus how tools might improve care. absolute necessity for multidisciplinary approach improving treatment strategies becoming more apparent our understanding biology deepens. ensures patients receive customized medicines fit their unique profiles. Future avenues investigation will resolving issues dealing efficacy results, ultimately leading disease cure patients.

Language: Английский

Citations

1
Irradiated microparticles suppress prostate cancer by tumor microenvironment reprogramming and ferroptosis DOI Creative Commons

Zihan Deng,

Binghui Li, Muyang Yang

et al.

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: May 5, 2024

Abstract Immunogenic cell death (ICD) plays a crucial role in triggering the antitumor immune response tumor microenvironment (TME). Recently, considerable attention has been dedicated to ferroptosis, type of ICD that is induced by intracellular iron and demonstrated change desert status TME. However, among cancers are characterized an desert, such as prostate cancer, strategies for inducing high levels ferroptosis remain limited. Radiated cell-derived microparticles (RMPs) radiotherapy mimetics have shown activate cGAS-STING pathway, induce inhibit M2 macrophage polarization. RMPs can also act carriers agents with biocompatibility. In present study, we designed therapeutic system wherein inducer RSL-3 was loaded into RMPs, which were tested vitro vivo carcinoma models established using RM-1 cells. The apoptosis CT20 peptide (CT20p) added aggravate ferroptosis. Our results showed RSL-3- CT20p-loaded (RC@RMPs) led Moreover, CT20p had synergistic effect on promoting reactive oxygen species (ROS) production, lipid hydroperoxide mitochondrial instability. RC@RMPs elevated dendritic (DC) expression MHCII, CD80, CD86 facilitated M1 subcutaneously transplanted model mice, inhibited growth prolonged survival time via DC activation, reprogramming, enhancement CD8 + T infiltration, proinflammatory cytokine production tumor. combination treatment anti-PD-1 improved inhibition. This study provides strategy cancer immunotherapies. Graphical

Language: Английский

Citations

7
Cyclin‐dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration‐resistant prostate cancer DOI Creative Commons
Haozhe Zhang, Yi Zhou, Yating Feng

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(5)

Published: May 1, 2024

Abstract Background Cyclin‐dependent kinase 12 (CDK12)‐deficient prostate cancer defines a subtype of castration‐resistant (CRPC) with poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this CRPC, and the underlying mechanism remains elusive. Methods Based on bioinformatics analysis, we evaluated relationship between CDK12 deficiency patient's prognosis resistance. Furthermore, used CRISPR‐Cas9 technology mass spectrometry‐based metabolomic profiling to reveal metabolic characteristics CDK12‐deficient CRPC. To elucidate specific mechanisms deficiency‐mediated CRPC reprogramming, utilized cell RNA‐seq other molecular biology techniques, cellular reactive oxygen species probes, mitochondrial function assays, ChIP‐qPCR RNA stability analyses, clarify role in regulating its contribution ferroptosis. Finally, through vitro drug sensitivity testing vivo experiments mice, identified therapeutic effects electron transport chain (ETC) inhibitor IACS‐010759 Results cancers reprogramme energy metabolism support their aggressive progression. In particular, enhanced respiratory electronic transfer ATP synthesis create ferroptosis potential cells. However, downregulated ACSL4 expression, which counteracts lipid oxidation stress, leading escape cells from targeting ETC substantially inhibited proliferation vivo, suggesting new target therapy cancer. Conclusions Our findings show that work together drive progression provide insight into worse patients. Key points promotes by reprogramming metabolism. leads more active (ETC), ensuring efficient supply. phosphorylates Pol II ensure transcription regulate Mitochondrial inhibitors exhibit better selectivity cells, offering promising approach

Language: Английский

Citations

6
Hydrophobic tagging of small molecules: an overview of the literature and future outlook DOI
Yang Zhou, Fan Zhou, Shujing Xu

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(7), P. 799 - 813

Published: June 2, 2024

Introduction Hydrophobic tagging (HyT) technology presents a distinct therapeutic strategy diverging from conventional small molecule drugs, providing an innovative approach to drug design. This review aims provide overview of the HyT literature and future outlook offer guidance for

Language: Английский

Citations

6