Prostate cancer (PCa) is the second most common cancer and second leading cause of cancer death for American men. Chemoprevention by using phytochemicals offers a promising approach to improve outcomes due to their ability to act on cancer cell metabolism and growth while maintaining low toxicity profiles. The goal of this study was to assess the combination of xanthohumol (XAN) and ursolic acid (UA) given in the diet for synergistic efficacy against PCa progression and identify potential mechanisms of action. PCa cells were treated with the combination to evaluate cell survival and colony formation. Two mouse models of PCa were used to evaluate tolerability and efficacy of dietary administration of the combination and to further understand mechanism(s) of action. The combination of XAN + UA reduced PCa cell survival and colony formation. The combination given in the diet significantly and synergistically inhibited growth of HMVP2 PCa allograft tumors and also inhibited PCa progression in HiMyc mice. Mechanistically, inhibition of polyamine synthesis and epithelial-to-mesenchymal transition contributed to the inhibition of HMVP2 allograft tumor growth, while the inhibition of PCa progression in HiMyc mice was associated with activation of the unfolded protein response pathway and apoptosis. Further studies in cultured PCa cells revealed additional effects of the combination on several oncogenic signaling pathways (e.g, phospho-STAT3) and cell cycle regulatory proteins (e.g, cyclin D1, phospho-Rb).

Targeting glycolysis in prostate cancer: Molecular mechanisms and therapeutic advances.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PCa), associated with poor prognosis and resistance to androgen receptor (AR)‑targeted therapies. Hypoxia is a well‑established driver of lineage plasticity and has been implicated in promoting NE differentiation (NED) of tumors. However, the underlying molecular mechanisms linking hypoxia to NED remain unclear. In the present study, miR‑135b‑5p was identified as a critical regulator of hypoxia‑induced NED through modulation of the hypoxia‑inducible factor alpha‑1 subunit alpha inhibitor (HIF1AN)‑HIF1α axis. Exposure of androgen‑dependent PCa cell lines (LNCaP and VCaP) to hypoxia induced neurite outgrowth and increased expression of NE markers, concurrent with upregulation of miR‑135b‑5p. Target prediction followed by experimental validation in luciferase reporter assays confirmed that HIF1AN is a direct target of miR‑135b‑5p. Suppression of HIF1AN results in the stabilization of HIF1α, which in turn activates the AKT/mTOR signaling pathway, facilitating NE trans differentiation. Functional studies demonstrated that overexpression of miR‑135b‑5p by mimics promotes NED in LNCaP cells, while inhibition of miR‑135b‑5p reverses the NE features in NE‑LNCaP and NCI‑H660, NE cells. Furthermore, pharmacological inhibition of HIF1α using PX‑478 abrogated hypoxia‑induced NED and attenuated activation of AKT/mTOR signaling, further underscoring the significance of the miR‑135b‑5p‑HIF1AN‑HIF1α axis in NED of PCa cells. Collectively, the findings of the present study reveal a novel miR‑135b‑5p‑HIF1AN‑HIF1α signaling axis that is involved in hypoxia‑induced NED via AKT/mTOR activation and identify miR‑135b‑5p and HIF1α as potential therapeutic targets for NEPC.

Cancer-associated fibroblasts promote immune evasion in pancreatic cancer via miR-181b-5p/STING/LGALS1 pathway.

Ginsenoside Rg3 synergizes with near-infrared photothermal therapy to suppress prostate cancer progression by inhibiting RAS signaling and enhancing ARL11-mediated macrophage reprogramming.

Effect of proton therapy and chemoradiotherapy on biochemistry of radioresistant prostate cancer cells studied by Raman microspectroscopy.

In this study, a series of novel iridium(III) complexes incorporating 2-phenylimidazo[4,5-f][1,10]phenanthroline ligands with different substituents (methyl (1a), isopropyl (2a), methoxy (3a), phenyl (4a)) were evaluated for their in vitro inhibitory activities against anticholinesterase (acetylcholinesterase [AChE], butyrylcholinesterase [BChE]) and carbonic anhydrase [hCA I] and [hCA II]) enzymes. Among the tested compounds, 2a demonstrated exceptional potency with IC50 values of 66.5 ± 9.06 nM for AChE and 26.45 ± 5.00 nM for BChE, significantly outperforming tacrine. Compound 4a also exhibited strong inhibition of hCA I (IC50 = 33.0 ± 7.09 nM) and hCA II (IC50 = 41.79 ± 8.09 nM), surpassing the reference drug acetazolamide. Molecular docking studies revealed that compound 4a exhibited the strongest binding affinity with BChE (PDB: 4BDS) at -12.06 kcal/mol, while compound 2a showed strong binding to hCA II (PDB: 3HS4) at -8.768 kcal/mol. Molecular dynamics simulations over 150 ns confirmed the structural stability of the protein-ligand complexes. Cell viability assays showed that compounds 1a-4a decreased PC3 prostate cancer cell viability in a concentration-dependent manner, with IC50 values of 10.09, 3.95, 11.39, and 4.51 µM, respectively. This comprehensive study highlights iridium(III) complexes as multitarget therapeutic agents with potent anticholinesterase and carbonic anhydrase inhibitory properties, offering promise for treating neurodegenerative and metabolic disorders.

M1C mediates LINE-1 transcription in PARP inhibitor-treated prostate cancer cells.

A2AR as a key target for immune microenvironment remodeling in prostate cancer.

Discovery of novel indole derivatives as LRH-1 antagonists for the treatment of castration resistant prostate cancer.

Arachidonic acid analog AACOCF3 suppresses cPLA2-negative NSCLC cell proliferation by targeting SSRP1 to activate the IFNα/β pathway.

To determine whether the MutT Homolog 1 (MTH1) inhibition could increase the sensitivity of Castration-Resistant Prostate Cancer (CRPC) cells to Radiotherapy (RT), as well as to determine the appropriate application time of the MTH1 inhibitor and RT to achieve optimal radiosensitizing effects. PC-3 and DU-145 cells were selected as the model cell lines for CRPC. After 24 h of incubation, the cells were treated with various doses of the MTH1 inhibitor TH287 for 72 h, during which they were subjected to Ionizing Radiation (IR) treatment at 12, 24, and 48 h after the initial drug treatment. Cell survival was evaluated through the Cell Counting Kit 8 (CCK-8) assay. Apoptotic induction and cell cycle progression were evaluated through Western Blotting (WB) and flow cytometry analyses. The CCK-8 assay revealed that the TH287 + IR combination therapy significantly inhibited PC3 and DU145 cell survival, with the most potent effects observed in the combined IR administration at 12 h (P < 0.05). Furthermore, Annexin-V/PI (Propidium Iodide) dual staining revealed that the TH287 + IR combination treatment induced apoptotic tumor cell death more effectively than either treatment alone (P < 0.05). Moreover, WB analysis revealed that the TH287 + IR combination therapy significantly altered caspase-3 expression, indicating DNA damage induction and modulation of various cell cycle-related proteins. Moreover, flow cytometry analysis revealed that the TH287 + IR treatment caused significant G2/S-phase arrest in prostate cancer cells (P < 0.05). Overall, TH287 exhibited potent radiosensitization effects for CRPC treatment, effectively killing tumor cells when administered alongside IR at 12 h after the initial drug treatment.

HIF-1α and YBX1 Mediated Up-Regulation of NonO/p54nrb in Prostate Cancer Cells.

In this study, we analyzed bioactive compounds from six edible wild mushrooms: Amanita caesarea, Amanita vaginata, Amanita rubescens, Clitocybe gibba, Laccaria laccata, and Ramaria apiculata. The fruiting bodies were used to extract the compounds using methanol. Qualitative screening revealed that anthraquinones are predominantly found in R. apiculata. The highest amounts of flavonoids and total phenols, were found in A. caesarea, (17.4 mg GAE/g and 205.0 mg GAE/g, respectively). When quantifying antioxidant activity using DPPH, no differences were observed, except in C. gibba. However, with ABTS, L. laccata showed the highest activity (402.6 ± 42.4 µM Trolox/mg). The biological activity of the fungal extracts was also evaluated. Toxicity assays on Artemia salina showed LD50 values ranging from 27.6 to 118.6 µg/mL, indicating variying levels of toxicity depending on the species. Moreover, the extracts showed cytotoxic on various cancer cell lines. Specifically, C. gibba exhibited activity against MCF-7, HCT-15, CaOV3, and HeLa cells; A. vaginata was effective against MCF-7 cells; and L. laccata showed activity against HCT-15 and PC3 cells. These findings indicate that the evaluated fungal extracts contain metabolites associated with antioxidant and in vitro cytotoxic activities. However, further chemical characterization and mechanistic studies are required before suggesting potential pharmacological applications.

Studies of natural products and their semisynthetic derivatives are a valuable source of therapeutic agents. The aim of this work was to obtain new 30-phosphoramidate derivatives of betulin and determine their biological potential. The synthetic approach utilized the Staudinger reaction (the introduction of a phosphoramidate group), the Steglich reaction (the introduction of an alkynyl group), and the Jones reaction (the introduction of a carboxyl group). The structures of the target compounds were determined using spectroscopic methods (1H NMR, 13C NMR, 31P NMR, and HRMS). The new derivatives were tested for antiproliferative activity against MV4-11, A549, MCF-7, PC-3, and HCT116 cancer cells and against normal MCF-10A cells using the MTT and SRB methods. Apoptosis studies were performed for the most active compounds (6B and 7A), potential molecular targets (AutoDock software) were identified, and lipophilicity parameters (RP-TLC method, SwissADME website) were determined. The greatest effect on apoptosis and caspase 3/7 activation was observed for the diester derivative 7A. Compound 7A showed a high lipophilicity parameter in the study group.

Due to their multifaceted biological effects, anthraquinones have attracted increasing interest as potential anticancer agents. In this study alizarin has been analyzed for its activity against cervical and prostate cancer cell models, which represent malignancies with a high global disease burden. The effects of alizarin were studied in HeLa and DU145 cell lines using both two- and three-dimensional culture systems. Morphological and ultrastructural analyses revealed changes characteristic of apoptosis, accompanied by increased caspase-3/7 activity, phosphorylation of the antiapoptotic protein Bcl-2, activation of ATM and H2A.X in response to DNA damage, inhibition of the PI3K/MAPK signaling pathway, and alterations in mitochondrial morphology associated with elevated reactive oxygen species generation. Alizarin also induced features consistent with mitotic catastrophe and modulated autophagy-related processes. A synergistic proapoptotic effect was observed when alizarin was combined with Venetoclax, a selective Bcl-2 inhibitor, resulting in enhanced cytotoxicity in both cervical and prostate cancer cell models. The antiproliferative effects of alizarin were further associated with inhibition of cell migration, reduction of the mitotic index, and alterations in cell cycle progression, including accumulation of cells in the G2/M phase. Comparable cytotoxic effects were also observed in three-dimensional spheroid cultures. Overall, these findings indicate that alizarin affects multiple cellular pathways involved in cancer cell survival and proliferation and may be of interest in the context of combination anticancer strategies, although further studies are required to clarify the underlying molecular mechanisms.

Single-cell proteomics (SCP) platforms are widely sought-after biomedical tools to complement existing omics technologies. Here, we present MiProChip, a microfluidic platform that integrates cell capture, lysis, protein digestion, tandem mass tag (TMT) labeling, on-chip pooling, and desalting a streamlined workflow for multiplexed SCP profiling. We optimized a chip-compatible TMT multiplexing protocol with a carrier-boosting strategy, enabling high-throughput operation and deep proteome coverage. MiProChip was designed to effectively reduce the mass spectrometry (MS) operation time, minimize adsorptive losses, enhance mixing, and stabilize flow for on-chip pooling, leading to a superior performance in recovery. Using PC9 and H1975 cells with a 100-cell carrier, a total of 3362 protein groups with 2775 ± 36 proteins were confidently identified across TMT-10-plex single-cell channels. Demonstration on murine colon adenocarcinoma cells identified 3199 proteins with 1669 ± 261 proteins per single cell to characterize galectin-8- and TGF-β-specific responses. Single-cell principal component analysis (PCA) showed separation of the control from treated groups, partial overlap between galectin-8 and TGF-β, and close clustering of TGF-β with the combination treatment, supporting a dominant TGF-β effect. Pathway enrichment analysis reveals their responsive pathway and distinguishes galectin-8- and TGF-β-specific responses, revealing downregulation of metastasis-related markers to support antimetastasis potential of galectin-8, which was not detected by bulk proteomic analysis. Collectively, MiProChip captured subtle proteomic heterogeneity and treatment-dependent single-cell responses, establishing a sensitive and robust platform for high-throughput SCP analysis.

Therapeutic management of prostate cancer remains challenging. Prostatic artery chemoembolization (PACE), an advanced minimally invasive technique derived from prostatic artery embolization (PAE), has shown promising potential in controling tumor growth and alleviating symptoms such as hematuria and lower urinary tract obstruction in prostate cancer, and has garnered widespread attention in recent research. However, preclinical progress is hindered by the limitations of existing animal models, and the development of a simple and reliable animal model to better understand the endovascular interventional treatment of prostate cancer is necessary. To develop and characterize a novel xenograft model of human prostate cancer in the rabbit auricle as a practical platform for experimental research on endovascular embolization techniques. Fresh human PC3 cell suspension (0.1ml containing ~ 9 × 106 cells) was injected subcutaneously into each auricle of 15 immunosuppressed New Zealand white rabbits. Tumor growth was measured periodically, and volume doubling time (VDT) was calculated. Digital subtraction angiography was performed via the central auricular artery when tumors were greater than 150mm3. Subsequently, histopathological and immunohistochemical analyses were conducted. Repeated-measures ANOVA was used to assess the significance of differences in the VDT of auricle tumors within-rabbits and between rabbits. The model achieved a high tumor take-rate of 86% (26/30 auricles). Angiography revealed distinct tumor-feeding vessels and uniform ring-like staining. Histopathology confirmed invasive growth of poorly differentiated, atypical tumor cells with high mitotic activity and no obvious necrosis. Immunohistochemistry showed high Ki67 expression (82.43 ± 3.68)%, indicating active proliferation. During the exponential growth stage, the mean VDT was 6.4 ± 1.8days. Repeated-measures ANOVA revealed significant variations in VDT among the rabbit subjects (P < 0.05); moreover, the VDT did not significantly differ between the left and right ears of each rabbit (P > 0.05), thereby reinforcing the consistency of the model employed. The rabbit auricle PC3 xenograft model is a valuable preclinical platform. It effectively simulates human prostate cancer with high reproducibility and clear vasculature, providing a foundational tool for subsequent investigations into the efficacy of endovascular therapies, such as PAE and PACE.

The emergence of the neuroendocrine phenotype in castration resistant prostate cancer (CRPC) is associated with poor patient prognosis. Castration-induced death of fully differentiated, androgen-sensitive PC cells might foster interactions among rare androgen-independent, poorly differentiated cancer cells and the extracellular matrix (ECM) that promotes the development of neuroendocrine PC (NEPC). Here, we investigated physical and molecular interactions between poorly differentiated PC cells with exocrine (PAC) or neuroendocrine features (PNE), which recapitulated pre-existing human CRPC-like cells, and decellularized prostate ECM. Without androgens, PAC cells and PC-derived ECM promoted in vitro invasiveness of PNE cells by inducing integrin α2 upregulation and YAP activation, indicating a cell-to-cell and cell-to-matrix contact-driven process. Inhibition of RANK/RANKL and NF-κB prevented integrin α2 upregulation in PNE cells, and integrin α2β1 and YAP inhibition also reduced PNE invasiveness. Microenvironment-conditioned PNE cells showed YAP-dependent metastatic behavior in vivo, and YAP inhibition suppressed the development of NEPC and metastasis in castration-naïve mice and of CRPC-NE in transgenic PC mice. Importantly, YAP inhibitors also restrained the growth of human CRPC organoids. These findings unveil mechanisms of NEPC development and implicate the integrin α2-YAP axis as a therapeutic target in PC patients receiving androgen-deprivation therapy.

Prostate cancer represents a prevalent urological malignancy, but the molecular mechanisms underlying the differentiation of distinct tumor cell subtypes have not been fully elucidated. We conducted an analysis of paired single-cell RNA sequencing data from the public database on prostate cancer, and discovered differentially expressed genes between tumor cells and normal epithelial cells. We evaluated the expression of SCGB1A1 in prostate cell lines and tissue samples, and assessed migration, invasion, and proliferation through CCK-8, EdU, wound healing, and Transwell experiments. We performed pathway enrichment analysis to explore the downstream mechanism of SCGB1A1 (Secretoglobin Family 1A Member 1). Single-cell transcriptomic analysis revealed a marked reduction in SCGB1A1⁺ epithelial cells within tumor tissues, accompanied by an increased abundance of KLK3⁺ tumor epithelial cells. SCGB1A1 expression was significantly downregulated in both prostate cancer cell lines and tumor epithelial cells. Functional assays demonstrated that SCGB1A1 overexpression suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of prostate cancer cells. SCGB1A1 expression is negatively correlated with the activation of the MAPK signaling pathway, which may be associated with its tumor-suppressive effects. Our findings identify SCGB1A1 as a previously underappreciated tumor-suppressive role in prostate cancer and reveal its role in modulating MAPK signaling and EMT. The depletion of SCGB1A1⁺ epithelial cells characterizes the malignant epithelial phenotype, suggesting its potential as a candidate diagnostic biomarker and therapeutic target that requires further clinical validation.