Prostate Cancer Cells Research Articles

Studying the impact of chitosan salicylaldehyde/schiff base/CuFe2O4 in PC3 cells via theoretical studies and inhibition of PI3K/AKT/mTOR signalling

In this elucidation, the nucleophilic attack of salicyladehyde with chitosan, which was obtained from the shrimp shell, afforded the cellulose aldehyde (Schiff base), and then the dispersion of CuFe2O4 on the surface of cellulose aldehyde gave the novel nanomaterial of bimetallic oxide, which was confirmed through spectral analysis such as FT-IR, NMR, SEM, and XRD analysis. Moreover, the anti-proliferative effect of chitosan, chitosan salicylaldehyde, and chitosan salicylaldehyde/CuFe2O4 was evaluated in PC3 human prostate cancer cells and HSF normal human skin fibroblasts. After 48 h, PC3 cell proliferation was significantly inhibited by chitosan salicylaldehyde/CuFe2O4 and chitosan salicylaldehyde (IC50 = 35.3 and 45.55 µg/ml, respectively) without any effects on normal HSF cells. The mRNA expression levels of PI3K, AKT, mTOR, and CCND1 were examined in PC3-treated cells by using QRT-PCR, and the results demonstrated that, by down-regulating the expression levels of these genes, chitosan salicylaldehyde/CuFe2O4 significantly affected prostate cancer cell proliferation, progression, and autophagy more than chitosan salicylaldehyde. Furthermore, the docking stimulation of the chitosan derivatives with different proteins showed the presence of CuFe2O4 particles effect on the interaction inside their pockets and increased the activities, and it’s related to biological evaluation. Additionally, the theoretical investigation of these chitosan derivatives and the determination of their physical descriptors showed the activity of bimetallic oxide and the presence of electrostatic hydrogen bond interaction. Finally, these findings may suggest that chitosan salicylaldehyde/CuFe2O4 has a promising anticancer impact against prostate cancer.

Targeted and Synergistic Codelivery of Chemotherapeutic and Nucleic Acid Drugs by Liposome-Coated MPDA Nanoparticles for Advanced Prostate Cancer Treatment.

Docetaxel (DTX)-based chemotherapy is the primary therapeutic approach for advanced prostate cancer (PCa) when endocrine therapy proves ineffective. Traditional chemotherapy exhibits poor specificity and induces severe side effects, such as immunosuppression, neurotoxicity, and hypersensitivity. In this study, we aimed to develop a new targeted nanodrug delivery system to accurately identify PCa cells and deliver drugs. We prepared mesoporous polydopamine (MPDA) nanoparticles using a one-pot method. After loading DTX onto MPDA, siRNA was attached to the surface, which was coated with polyethylene glycol lipids film (PEG-Lips); together, this formed MDS@L. The aptamer A10-3.2 was coupled to the surface of PEG-Lips to obtain MDS@LA, which was characterized using different techniques, including transmission electron microscopy and Fourier transform infrared spectroscopy. MDS@LA exhibited excellent stability, acid-responsive release, and photothermal properties, enhancing its antitumor effects. Both in vitro and in vivo experiments revealed that MDS@LA precisely targeted PCa cells and effectively delivered DTX and siRNA, leading to significant inhibition of PCa cell growth and proliferation. This versatile nanoplatform offers a promising, precise, and efficient therapeutic approach for advanced PCa, addressing the limitations of conventional chemotherapy.

Transient flow-induced deformation of cancer cells in microchannels: a general computational model and experiments.

Recently, the present authors proposed a three-dimensional computational model for the transit of suspended cancer cells through a microchannel (Wang et al. in Biomech Model Mechanobiol 22: 1129-1143, 2023). The cell model takes into account the three major subcellular components: A viscoelastic membrane that represents the lipid bilayer supported by the underlying cell cortex, a viscous cytoplasm, and a nucleus modelled as a smaller microcapsule. The cell deformation and its interaction with the surrounding fluid were solved by an immersed boundary-lattice Boltzmann method. The computational model accurately recovered the transient flow-induced deformation of the human leukaemia HL-60 cells in a constricted channel. However, as a general modelling framework, its applicability to other cell types in different flow geometries remains unknown, due to the lack of quantitative experimental data. In this study, we conduct experiments of the transit of human prostate cancer (PC-3) and leukaemia (K-562) cells, which represent solid and liquid tumour cell lines, respectively, through two distinct microchannel geometries, each dominated by shear and extension flow. We find that the two cell lines have qualitatively similar flow-induced dynamics. Comparisons between experiments and numerical simulations suggest that our model can accurately predict the transient cell deformation in both geometries, and that it can serve as a general modelling framework for the dynamics of suspended cancer cells in microchannels.

The Pro-Migratory and Pro-Invasive Roles of Cancer-Associated Fibroblasts Secreted IL-17A in Prostate Cancer.

Cancer-associated fibroblasts (CAFs) are key stroma cells that play dominant roles in the migration and invasion of several types of cancer through the secretion of inflammatory cytokine IL-17A. This study aims to identify the potential role and regulatory mechanism of CAFs-secreted IL-17A in the migration and invasion of prostate cancer (PC). CAFs and normal fibroblasts (NFs) were obtained from fresh PC and its adjacent normal tissues, respectively. PC cells LNCaP and DU145 were co-cultured with the conditioned medium from the CAFs and NFs. IL-17A level was determined by ELISA in the cell supernatant. CCK-8, wound healing, Transwell assay, western blot analysis, staining, and primary PC lung metastasis assays were employed in vivo or in vitro to explore the effect of CAFs and IL-17A secreted by them on proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) and metastasis of PC. CAFs stimulated the migration and invasion of PC cells. Importantly, CAFs exerted their roles by directly secreting IL-17A, leading to a significant increase in migration and invasion in PC cells. Mechanically, IL-17A promoted Smad3/p38 MAPK pathway-mediated EMT process, contributing to cell migration and invasion. Furthermore, CAFs secreting IL-17A activated the Smad3/p38 MAPK pathway and thus facilitated tumor growth and metastasis in nude mice. This study identifies a novel signaling pathway by which CAFs mediate migration and invasion of PC via upregulation of Smad3/p38 MAPK-mediated EMT in an IL-17A-dependent manner.

Innovative Hybrid Nanocarriers of GnRH Peptide-Modified Chitosan-Coated Lipid Nanoparticles as a Targeted Chemotherapy for Reproductive-Related Cancers.

Cancer stands as a primary contributor to worldwide mortality, especially reproductive-related cancers (e.g., breast/cervical cancers among females and prostate cancer among males). Chemotherapy is the most common systemic therapy for cancer, but its adverse effects are concerning. Developing effective and new strategies against cancer is necessary to increase their efficacy and minimize their adverse effect. In this work, the novel core-shell structure of lipid nanoparticle (LNP) was fabricated via a high-throughput microfluidic for chemotherapy drug delivery. A gonadotropin-releasing hormone (GnRH), a targeting moiety for the overexpressed GnRH receptors (GnRHR) in cancer cells, was conjugated on chitosan (GnRH-CS) as a shell and used to modify the surface of LNP with doxorubicin loading to form a complex of LNP-dox-GnRH (≤ 150 nm, PDI ~0.2). The modified surface enhances the binding affinity of the LNP to the breast and prostate cancer cells. For an invitro study, we found that LNP-dox-GnRH can specifically target the GnRHR-overexpressing cancer cells (i.e., MCF-7 and PC-3) compared with non-targeted LNP-dox. Conversely, there was no difference in the targetability between LNP-dox-GnRHR and non-targeted LNP to MDA-MB-436, a low GnRHR-expressing cancer cell. Furthermore, the enhanced anticancer activity of LNP-dox-GnRH was observed in both monolayer and spheroid cell cultures. This study highlights the advantages of easy customization of payloads and targeting peptides, requiring only a simple coating process that doesn't need specialized expertise. Its flexibility and efficiency enhance the potential for precision therapies, making it ideal for translational applications in treating reproductive-related cancers, GnRH-associated diseases, and other conditions.

ECM-mimicking hydrogel models of human adipose tissue identify deregulated lipid metabolism in the prostate cancer-adipocyte crosstalk under antiandrogen therapy.

Antiandrogen therapies are effectively used to treat advanced prostate cancer, but eventually cancer adaptation drives unresolved metastatic castration-resistant prostate cancer (mCRPC). Adipose tissue influences metabolic reprogramming in cancer and was proposed as a contributor to therapy resistance. Using extracellular matrix (ECM)-mimicking hydrogel coculture models of human adipocytes and prostate cancer cells, we show that adipocytes from subcutaneous or bone marrow fat have dissimilar responses under the antiandrogen Enzalutamide. We demonstrate that androgen receptor (AR)-dependent cancer cells (LNCaP) are more influenced by human adipocytes than AR-independent cells (C4-2B), with altered lipid metabolism and adipokine secretion. This response changes under Enzalutamide, with increased AR expression and adipogenic and lipogenic genes in cancer cells and decreased lipid content and gene dysregulation associated with insulin resistance in adipocytes. This is in line with the metabolic syndrome that men with mCRPC under Enzalutamide experience. The all-human, all-3D, models presented here provide a significant advance to dissect the role of fat in therapy response for mCRPC.

Ethacrynic acid inhibits the growth and proliferation of prostate cancer cells by targeting GSTP1 and regulating the PI3K-AKT signaling pathway.

As a diuretic, ethacrynic acid (EA) has been shown to play a suppressive role in cancers, including prostate cancer (PC). However, its molecular regulatory mechanism is still unclear. Therefore, our study is centered on investigating the effect of EA on PC development and its mechanism. To verify the binding relationship between EA and GSTP1, molecular docking and cellular thermal shift assay (CETSA) were conducted. To examine how EA affects PC cell proliferation, cell cycle, and apoptosis, cell function assays were performed. qRT-PCR was used to detect GSTP1 mRNA expression. The expression of GSTP1 protein and PI3K-AKT signaling pathway-related proteins in cells was detected by western blot (WB). To verify how EA and GSTP1 influence cell growth in PC, in vivo experiments were conducted. The binding relationship between GSTP1 and EA was confirmed by molecular docking and CETSA results. Cell experiments showed that EA could hinder PI3K/AKT pathway and PC cell proliferation, arrest the cell cycle in G0/G1 phase, and facilitate apoptosis by binding to GSTP1. In vivo experiments in nude mice verified that the interaction between EA and GSTP1 reduced PI3K and AKT phosphorylation and inhibited the growth of PC cells. EA inhibits PC progression by binding to GSTP1 to downregulate the activity of PI3K/AKT pathway, and this result suggests the potential of EA to be an anticancer agent for PC therapy.

A Modular Customizable Ligand-Conjugate (LC) System Targeting Ghrelin O-Acyltransferase

Ghrelin is a 28 amino acid peptide hormone that impacts a wide range of biological processes, including appetite regulation, glucose metabolism, growth hormone regulation, and cognitive function. To bind and activate its cognate receptor, ghrelin must be acylated on a serine residue in a post-translational modification performed by ghrelin O-acyltransferase (GOAT). GOAT is a membrane-bound O-acyltransferase (MBOAT) responsible for the catalysis of the addition of an octanoyl fatty acid to the third serine of desacyl ghrelin. Beyond its canonical role for ghrelin maturation in endocrine cells within the stomach, GOAT was recently reported to be overexpressed in prostate cancer (PCa) cells and detected at increased levels in the serum and urine of PCa patients. This suggests GOAT can serve as a potential route for the detection and therapeutic targeting of PCa and other diseases that exhibit GOAT overexpression. Building upon a ghrelin mimetic peptide with nanomolar affinity for GOAT, we developed an antibody-conjugate-inspired system for customizable ligand-conjugate (LC) synthesis allowing for the attachment of a wide range of cargoes. The developed synthetic scheme allows for the easy synthesis of the desired LCs and demonstrates that our ligand system tolerates an extensive palette of cargoes while maintaining nanomolar affinity against GOAT.

Analysing DNA methylation and transcriptomic signatures to predict prostate cancer recurrence risk.

Prostate cancer (PCa) remains a significant global health challenge, with approximately 1.6 million new cases and 366,000 deaths annually. Despite high survival rates for localized prostate cancer, recurrence poses a substantial risk due to inherent biological factors and residual disease. Early detection and intervention are essential for enhancing patient outcomes and reducing mortality. However, traditional diagnostics such as PSA tests, digital rectal examinations, and biopsies often lack specificity resulting in overdiagnosis. There is a pressing need for novel biomarkers to enhance precision medicine approaches for PCa. This study employs a machine learning approach to identify DNA methylation and RNA expression biomarkers predictive of PCa recurrence using datasets from The Cancer Genome Atlas (TCGA). We analyzed 49,133 genes, identifying 684 differentially methylated genes (DMGs) and 691 differentially expressed genes (DEGs) between recurrence and non-recurrence groups. Ten genes (TNNI2, SPIN2, COL5A3, RNF169, CCND1, FGFR1, SLC17A2, FAMM71F2, RREB1, AOX1) were found to have significant correlations between methylation and expression, forming the basis for our predictive model. A support vector machine (SVM) model was developed using these ten genes, achieving an area under the curve (AUC) of 0.773, demonstrating robust predictive capability. Multivariate regression analysis confirmed the SVM score as an independent predictor of recurrence (HR = 0.45; 95% CI 0.28-0.69, P < 0.001). The analysis of recurrence-free survival suggested that patients with low-risk scores experienced significantly better outcomes compared to those with high-risk scores. Functional enrichment analyses of DMGs revealed significant involvement in biological processes such as transcription regulation, signal transduction, and immune response, highlighting the potential mechanistic pathways of these biomarkers. Validation using real-time PCR confirmed differential expression and methylation patterns of the identified genes in prostate cancer (PC3) and non-cancerous cell lines (PNT2). In conclusion, our study hihglights the DNA methylation biomarkers linked to PCa recurrence and introduces a promising SVM model for early prediction, potentially improving treatment outcomes. Further research is needed to explore the biological roles of these genes in PCa aiming to refine therapeutic approaches.

β-Elemene inhibits epithelial-mesenchymal transformation in non-small cell lung cancer by targeting ALDH3B2/RPSA axis.

The pharmacological mechanism of β-elemene in non-small cell lung cancer (NSCLC) remains poorly understood. In this study, we identified aldehyde dehydrogenase 3B2 (ALDH3B2) as a pivotal target for β-elemene's anti-tumor effects in NSCLC by bioinformatic analysis. The overexpression of ALDH3B2 is specifically associated with the malignancy of NSCLC and the poor prognosis in patients with lung adenocarcinoma. Furthermore, we observed a positive correlation between ALDH3B2 levels and the sensitivity of cells to β-elemene. Additionally, we confirmed that β-elemene suppresses ALDH3B2 expression in PC-9 and NCI-H1373 cell lines. Notably, ALDH3B2 overexpression in NCI-H1373 cells resulted in enhanced migration, invasion, and a prominent epithelial-mesenchymal transition (EMT), which could be attenuated by β-elemene via inhibition of ALDH3B2 expression. Subsequent investigations demonstrated that ALDH3B2 overexpression upregulated ribosomal protein SA (RPSA) expression. β-elemene counteracted the upregulation of RPSA by suppressing ALDH3B2. Furthermore, knocking down of ALDH3B2 and β-elemene treatment significantly reduced the activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathways via suppression of RPSA. In summary, our research uncovers that in NSCLC, ALDH3B2 functions as an oncogenic protein, promoting tumor progression. Meanwhile, β-elemene inhibits EMT of NSCLC by inhibition of ALDH3B2/RPSA axis and subsequently downregulating AKT and ERK signaling pathways. Our study highlights the significant role of ALDH3B2 in the progression of NSCLC, signifying it as a potential pharmacodynamic biomarker for β-elemene. These findings enrich the understanding of anti-tumor pharmacological mechanism of β-elemene, and provides new theoretical and experimental foundations for its potential application in the treatment of NSCLC.

Polyphyllin VII Enhances the Sensitivity of Prostate Cancer Cells to Docetaxel by Promoting Mitochondrial Dysfunction and Inducing Ferroptosis.

Docetaxel (DTX) is the preferred chemotherapeutic drug for prostate cancer (Pca), but the emergence of resistance has significantly reduced its efficacy. Polyphyllin VII (PPVII), a small molecule natural product derived from the traditional herb Paris polyphylla, has shown anticancer potential. This study aims to investigate the effects and mechanisms of PPVII combined with DTX in treating Pca. DTX-sensitive DU-145 cells and DTX-resistant DU145/DTX cells were utilized for experiments in this study. Cell viability was assessed using MTT assays, while apoptosis, cell cycles, and ferroptosis were analyzed through flow cytometry and Western blot. Mitochondrial function was evaluated using immunofluorescence. Additionally, the expression of proteins related to the AMP-activated protein kinase/mammalian target of the rapamycin/S6 kinase (AMPK/mTOR/S6K) signaling pathway was also examined to further investigate the underlying mechanisms. PPVII significantly enhanced the inhibitory effect of DTX, reduced cell viability (p < 0.05), and promoted apoptosis (p < 0.05) and cell cycle arrest (p < 0.05). Specifically, PPVII increased the sensitivity of Pca cells to DTX by inducing ferroptosis and affecting mitochondrial function. Notably, the activation of the AMPK/mTOR/S6K signaling pathway played a crucial role in this process. This study revealed the synergistic effects and potential mechanisms of PPVII combined with DTX in Pca cells, and provided a reference for effectively overcoming DTX resistance in the clinical treatment of Pca.

Metabolic reprogramming, malignant transformation and metastasis: Lessons from chronic lymphocytic leukaemia and prostate cancer.

Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis. This review considers glucose and lipid metabolism in CLL and prostate cancer, exploring their roles in healthy and malignant states and during disease progression. In CLL, lipid metabolism supports cell survival and migration, with aggressive disease characterised by increased fatty acid oxidation and altered sphingolipids. Richter's transformation and aggressive lymphoma, however, exhibit a metabolic shift towards increased glycolysis. Similarly, prostate cell metabolism is unique, relying on citrate production in the healthy state and undergoing metabolic reprogramming during malignant transformation. Early-stage prostate cancer cells increase lipid synthesis and uptake, and decrease glycolysis, whereas metastatic cells re-adopt glucose metabolism, likely driven by interactions with the tumour microenvironment. Genetic drivers including TP53 and ATM mutations connect metabolic alterations to disease severity in these two malignancies. The bone microenvironment supports the metabolic demands of these malignancies, serving as an initiation niche for CLL and a homing site for prostate cancer metastases. By comparing these malignancies, this review underscores the importance of metabolic plasticity in cancer progression and highlights how CLL and prostate cancer may be models of circulating and solid tumours more broadly. The metabolic phenotypes throughout cancer cell transformation and metastasis, and the microenvironment in which these processes occur, present opportunities for interventions that could disrupt metastatic processes and improve patient outcomes.

Antibody‑drug conjugates in prostate cancer: Emerging strategies to enhance therapeutic index and current clinical landscape (Review).

The global incidence of prostate cancer (PCa) is rising. Localized PCa can be managed through surgical intervention or radiotherapy, but certain patients may experience recurrence or develop metastatic disease following localized treatment. Despite aggressive therapeutic approaches, the majority of metastatic patients with PCa will eventually progress to metastatic castration‑resistant PCa, with limited treatment alternatives and a dismal prognosis. The treatment options for advanced PCa are continuously evolving, yet there remains a demand for further innovative therapeutic approaches. Antibody‑drug conjugates (ADCs) represent a novel class of targeted medications comprising a humanized monoclonal antibody, a linker and a cytotoxic payload. ADCs primarily bind to antigens that are upregulated on the surface of PCa cells but are minimally expressed on normal cells. At present, a variety of targets for ADCs have been identified in the treatment of PCa, encompassing prostate‑specific membrane antigen, STEAP family member 1, trophoblast cell‑surface antigen 2, CD46, B7‑H3, tissue factor and delta‑like protein 3, each with one or more specific ADC that has shown encouraging results in the PCa field. In the present review, the developmental course, composition and mechanism of action of ADCs are explored, with a specific focus on recently published studies and ongoing trials aimed at investigating the efficacy and safety of ADCs in treating PCa. Lastly, ongoing challenges in ADC development and corresponding strategies to combat them are discussed.

Trillin inhibits MAP3K11/NF-κB/COX-2 signaling pathways through upregulation of miR-145-5p in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) presents a significant challenge in treatment following androgen deprivation therapy. This study evaluates Trillin, a compound with antioxidant and anti-inflammatory properties, for its therapeutic potential against CRPC. Using DU145 and PC3 cell lines and a mouse xenograft model, we demonstrate that Trillin effectively inhibits CRPC cell viability, proliferation, migration, and invasion while promoting apoptosis and cell-cycle arrest. Mechanistic investigations reveal that Trillin disrupts NF-κB/COX-2 signaling by downregulating MAP3K11 and COX-2 and inhibiting the nuclear translocation of NF-κB subunits. Additionally, Trillin enhances the expression of miR-145-5p, further modulating pathways critical for CRPC progression. These findings suggest that Trillin may offer a promising alternative approach for targeting CRPC, highlighting its potential as a therapeutic agent to improve patient outcomes.

Synergistic anti-cancer effects of piezoelectric hexagonal boron nitride nanocarriers for controlled doxorubicin release.

This study aims to develop a piezoelectric drug delivery system based on hexagonal boron nitride nanosheets (hBNs). hBNs were synthesized using the chemical vapor deposition (CVD) method and characterized through imaging and spectroscopic techniques. Their piezoelectric properties were evaluated to confirm their functionality. Subsequently, the potential of hBNs as nanocarriers was assessed through in vitro experiments with doxorubicin (Dox) as a model drug. The piezoelectric hBNs were successfully synthesized and exhibited efficient loading and controlled release of Dox. In vitro experiments conducted on PC3 (human prostate cancer) and PNT1A (normal adult prostate epithelial) cell lines demonstrated that ultrasound (US)-induced Dox-loaded hBNs (hBN-Dox) significantly inhibited the proliferation of prostate cancer cells, achieving efficacy at a much lower Dox concentration compared to conventional methods. The system enhanced reactive oxygen species (ROS) generation, impaired cancer cell colony formation, and induced both early and late apoptosis. These findings highlight the potential of piezoelectric hBNs as nanocarriers for efficient drug delivery, leveraging the synergistic effect of piezoelectricity-induced drug release and the degradation products of hBNs in biological media. Their ability to enhance drug efficacy while reducing the required dose holds promise for advanced cancer therapies.

CRM1 regulates androgen receptor stability and impacts DNA repair pathways in prostate cancer, independent of the androgen receptor.

Among the known nuclear exportins, CRM1 is the most studied prototype. Dysregulation of CRM1 occurs in many cancers, hence, understanding the role of CRM1 in cancer can help in developing synergistic therapeutics. The study investigates how CRM1 affects prostate cancer growth and survival. It examines the role of CRM1 in regulating androgen receptor (AR) and DNA repair in prostate cancer. Our findings reveal that CRM1 influences AR mRNA and protein stability, leading to a loss of AR protein upon CRM1 inhibition. Furthermore, it highlights the involvement of HSP90 alpha, a known AR chaperone, in the CRM1-dependent regulation of AR protein stability. The combination of CRM1 inhibition with an HSP90 inhibitor demonstrates potent effects on decreasing prostate cancer cell growth and survival. The study further explores the influence of CRM1 on DNA repair proteins and proposes a strategy of combining CRM1 inhibitors with DNA repair pathway inhibitors to decrease prostate cancer growth. Overall, the findings suggest that CRM1 plays a crucial role in prostate cancer growth, and a combination of inhibitors targeting CRM1 and DNA repair pathways could be a promising therapeutic strategy.

Hsa_circ_0030568 Promotes the Proliferation and Migration of Prostate Cancer Cells via the miR-141-3p-BRD4 Axis.

Numerous studies have indicated that circular RNAs (circRNAs) play an important role in diverse cancers. However, the specific molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unclear. In this study, we performed western blotting, real-time quantitative polymerase chain reaction, CCK-8 assay, cell scratch wound assay, and RNA immunoprecipitation assay. These results showed that the expression of hsa_circ_0030568 was remarkably increased in PCa cells by using quantitative real-time PCR combined with dataset analysis. Mechanistically, circ_0030568 could physically bind to miR-141-3p and elevate the expression of BRD4 via sponging miR-141-3p in PCa cells, then accelerating the progression of PCa. Upregulation of hsa_circ_0030568 induces tumor progression through the miR-141-3p-BRD4 axis. Taken together, these findings suggested that hsa_circ_0030568 may act as a potential biomarker of PCa and a promising target for PCa treatment.

Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth

Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.

A Unique Prodrug Targeting the Prostate-Specific Membrane Antigen for the Delivery of Monomethyl Auristatin E.

Monomethyl auristatin E (MMAE) is a promising treatment option for patients diagnosed with prostate cancer (PCa); however, toxicities prevent MMAE from being administered as free drug. No MMAE-based treatment is currently marketed for PCa. Herein, we describe a small-molecule-drug conjugate, CTT2274, for the selective delivery of MMAE. CTT2274 is composed of a prostate-specific membrane antigen (PSMA)-binding scaffold, a biphenyl motif, a pH-sensitive phosphoramidate linker, and MMAE payload. We demonstrate that CTT2274 shows selective binding to PSMA, which is overexpressed on PCa cells, and induces tumor cell death in vitro. In a patient-derived xenograft tumor model of PCa in mice, we show that weekly intravenous dosing of CTT2274 at 3.6 mg/kg for six weeks is superior to treatment with free MMAE at equivalent doses. Mice treated with CTT2274 experienced prolonged tumor suppression and significantly greater overall survival than mice treated with PBS. Additionally, the safety of CTT2274 compared to an equivalent dose of MMAE was assessed in healthy, non-tumor-bearing mice. Our results demonstrate that CTT2274 therapy is as efficacious as MMAE, results in superior overall survival, and has a more favorable safety profile. Together, these data indicate that CTT2274 is a candidate for clinical translation for the treatment of PCa.

VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis

Ferroptosis is a form of iron-dependent programmed cell death, which is distinct from apoptosis, necrosis, and autophagy. Mitochondria play a critical role in initiating and amplifying ferroptosis in cancer cells. Voltage-Dependent Anion Channel 1 (VDAC1) embedded in the mitochondrial outer membrane, exerts roles in regulation of ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating ferroptosis are not well elucidated. Here, we identify that a VDAC1 binding protein V-Set and Transmembrane Domain Containing 2 Like (VSTM2L), mainly localized to mitochondria, is positively associated with prostate cancer (PCa) progression, and a key regulator of ferroptosis. Moreover, VSTM2L knockdown in PCa cells enhances the sensitivity of RSL3-induced ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and hexokinase 2 (HK2), enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for mitochondria-localized VSTM2L in driving ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.