Inhibits Prostate Cancer Cell Growth Research Articles

A noncanonical E3 ubiquitin ligase RNF41-mediated MYO1C stability promotes prostate cancer metastasis by inducing actin remodeling.

Prostate cancer bone metastasis is a predominant cause of death for prostate cancer (PCa) patients. However, the underlying mechanisms are poorly understood. Here, we report that high levels of RNF41 are associated with metastatic human prostate cancer. RNF41 silencing inhibits prostate cancer cell growth, cell migration and invasion in vitro and in vivo. Mechanistically, we identify that RNF41 induces K27- and K63-linked noncanonical polyubiquitination of MYO1C to enhance its stability and induce actin remodeling, which promotes PCa bone metastasis. RNF41 was significantly upregulated in metastatic prostate cancer tissues and positively associated with MYO1C expression. Furthermore, we show in intraarterial injected-bone metastasis xenograft model that targeting MYO1C stability by inhibition of RNF41 markedly suppressed PCa bone metastasis. Collectively, our findings identify RNF41 is an important regulator of prostate cancer cell growth and metastasis and targeting RNF41/MYO1C could be a valuable strategy to ameliorate prostate cancer progression and metastasis.

USP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity

Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here, we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer (PCa). USP11 expression was up-regulated in metastatic PCa and CRPC. USP11 knockdown (KD) significantly inhibited PCa cell growth. Our RNA-seq studies revealed AR and c-Myc as the top transcription factors altered after USP11 KD. ChIP-seq analysis showed that either USP11 KD or replacement of endogenous USP11 with a catalytic-inactive USP11 mutant significantly decreased chromatin binding by AR and c-Myc. We find that USP11 employs two mechanisms to up-regulate AR and c-Myc levels: namely, deubiquitination of AR and c-Myc proteins to increase their stability and deubiquitination of H2A-K119Ub, a repressive histone mark, on promoters of AR and c-Myc genes to increase their transcription. AR and c-Myc reexpression in USP11-KD PCa cells partly rescued cell growth defects. Thus, our studies reveal a tumor-promoting role for USP11 in aggressive PCa through upregulation of AR and c-Myc activities and support USP11 as a potential target against PCa.

Hyperoside Inhibits RNF8-mediated Nuclear Translocation of β-catenin to Repress PD-L1 Expression and Prostate Cancer.

Hyperoside is a flavonol glycoside isolated from Hypericum perforatum L. that has inhibitory effects on cancer cells; however, its effects on prostate cancer (PCa) remain unclear. Therefore, we studied the anti-PCa effects of hyperoside and its underlying mechanisms in vitro and in vivo. This study aimed to explore the mechanism of hyperoside in anti-PCa. 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT), transwell, and flow cytometry assays were used to detect PCa cell growth, invasion, and cell apoptosis. Immunoblot analysis, immunofluorescence, immunoprecipitation, and quantitative real-time PCR (qRT-PCR) were used to analyze the antitumor mechanism of hyperoside. Hyperoside inhibited PCa cell growth, invasion, and cell cycle and induced cell apoptosis. Furthermore, RING finger protein 8 (RNF8), an E3 ligase that assembles K63 polyubiquitination chains, was predicted to be a direct target of hyperoside and was downregulated by hyperoside. Downregulation of RNF8 by hyperoside impeded the nuclear translocation of β-catenin and disrupted the Wnt/β-catenin pathway, which reduced the expression of the target genes c-myc, cyclin D1, and programmed death ligand 1 (PD-L1). Decreased PD-L1 levels contributed to induced immunity in Jurkat cells in vitro. Finally, in vivo studies demonstrated that hyperoside significantly reduced tumor size, inhibited PD-L1 and RNF8 expression, and induced apoptosis in tumor tissues of a subcutaneous mouse model. Hyperoside exerts its anti-PCa effect by reducing RNF8 protein, inhibiting nuclear translocation of β-catenin, and disrupting the Wnt/β-catenin pathway, in turn reducing the expression of PD-L1 and improving Jurkat cell immunity.

Prostate transmembrane androgen inducible protein 1 (PMEPA1): regulation and clinical implications.

Prostate transmembrane androgen inducible protein 1 (PMEPA1) can promote or inhibit prostate cancer cell growth based on the cancer cell response to the androgen receptor (AR). Further, it can be upregulated by transforming growth factor (TGF), which downregulates transforming growth factor-β (TGF-β) signaling by interfering with R-Smad phosphorylation to facilitate TGF-β receptor degradation. Studies have indicated the increased expression of PMEPA1 in some solid tumors and its functioning as a regulator of multiple signaling pathways. This review highlights the multiple potential signaling pathways associated with PMEPA1 and the role of the PMEPA1 gene in regulating prognosis, including transcriptional regulation and epithelial mesenchymal transition (EMT). Moreover, the relevant implications in and outside tumors, for example, as a biomarker and its potential functions in lysosomes have also been discussed.

Identification of the mitochondrial protein POLRMT as a potential therapeutic target of prostate cancer

RNA polymerase mitochondria (POLRMT) is essential for mitochondrial transcription machinery and other mitochondrial functions. Its expression and potential functions in prostate cancer were explored here. The Cancer Genome Atlas prostate cancer cohort (TCGA PRAD) shows that POLRMT mRNA expression is upregulated in prostate cancer tissues and POLRMT upregulation is correlated with poor patients’ survival. POLRMT mRNA and protein levels were upregulated in local prostate cancer tissues and different primary/immortalized prostate cancer cells. Genetic depletion of POLRMT, using viral shRNA or CRISPR/Cas9 gene editing methods, impaired mitochondrial functions in prostate cancer cells, leading to mitochondrial depolarization, oxidative stress, mitochondria complex I inhibition, and ATP depletion. Moreover, POLRMT depletion resulted in robust inhibition of prostate cancer cell viability, proliferation, and migration, and provoked apoptosis. Conversely, prostate cancer cell proliferation, migration, and ATP contents were strengthened following ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus impeded prostate cancer xenograft growth in nude mice. POLRMT silencing, oxidative stress, and ATP depletion were detected in POLRMT shRNA-treated prostate cancer xenograft tissues. IMT1 (inhibitor of mitochondrial transcription 1), the first-in-class POLRMT inhibitor, inhibited prostate cancer cell growth in vitro and in vivo. Together, overexpressed POLRMT is an important mitochondrial protein for prostate cancer cell growth, representing a novel and promising diagnostic and therapeutic oncotarget.

Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth

Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo.

Berbamine Inhibits the Biological Activities of Prostate Cancer Cells by Modulating the ROS/NF-κB Axis.

This study aimed to explore the mechanism of berbamine in inhibiting prostate cancer. Prostate cancer cell lines PC-3 and DU145 cells were used to evaluate the effects of berbamine. Cell viability was determined using cell-counting kit 8. The intracellular reactive oxygen species (ROS) levels were measured using a ROS assay kit. Cell apoptosis rate was examined using flow cytometry. The protein levels associated with cell proliferation, NF-κB pathway, and apoptosis were determined using western blot. It was found that berbamine induced cell cycle arrest in the S phase and inhibited prostate cancer cell growth and proliferation. Berbamine inhibited prostate cancer cells by inhibiting the activation of the NF-κB pathway in vitro. Berbamine increased ROS as an upstream molecule that inhibited the NF-κB pathway. Our results demonstrated that berbamine can effectively reduce the proliferation of prostate cancer cells. The ROS/NF-κB axis plays a crucial role in berbamine-mediated anti-prostate cancer cell proliferation.

A mononuclear N,N,N,O donor schiff base Cu(II) complex inhibits bacterial biofilm formation and promotes apoptosis and cell cycle arrest in prostate cancer cells

In this work, we report a distorted square pyramidal mononuclear copper(II) complex [Cu(L)(NCS)] (1) which was obtained by the reaction of the aqueous solution of ammonium thiocyanate to a methanolic solution of copper nitrate trihydrate and corresponding Schiff-base ligands. Schiff bases, HL (C12H19N3O) act as a tetradentate Schiff base, derived from 1:1 condensation of o-hydroxyacetophenone and diethylenetriamine. The synthesized complex has been successfully characterized based on elemental analysis and Infrared (IR) spectroscopy. The structure of complex 1 was confirmed by single-crystal X-ray diffraction study. In our study, we investigated synthesis, structural characterization, antimicrobial, anti-biofilm, and anti-cancer activity, and plausible mechanism of action of a novel mononuclear copper(II) schiff base complex. Increasing microbial resistance to several commercially available or traditional antimicrobial compounds has become a major global health concern at present time. The mononuclear copper(II) complex exhibited potential antibacterial activity against two strains of the gram-negative pathogen Pseudomonas aeruginosa. The copper compound dependent damage of bacterial cell membrane and inhibition of bacterial biofilm formation were also identified. Moreover, complex 1 inhibited prostate cancer cell growth, and migration by inducing apoptosis and arresting the cell cycle at the G2/M phase. Based on the results, we are suggesting our novel mononuclear copper(II) compound as a potential candidate for the development of new antibacterial and anti-cancer drugs.

Saw Palmetto may fight prostate cancer.

Saw Palmetto may fight prostate cancer.

DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent Pathway.

Epigenetic alterations such as DNA methylation and histone modifications are implicated in repressing several tumor suppressor genes in prostate cancer progression. In this study, we determined the anti-prostate cancer effect of a small molecule drug guadecitabine (gDEC) that inhibits/depletes the DNA methylation writer DNA methyltransferase 1 (DNMT1). gDEC inhibited prostate cancer cell growth and proliferation in vitro without activating the apoptotic cascade. Molecular studies confirmed DNMT1 depletion and modulated epithelial-mesenchymal transition markers E-cadherin and β-catenin in several prostate cancer cell lines (LNCaP, 22Rv1, and MDA PCa 2b). gDEC treatment also significantly inhibited prostate tumor growth in vivo in mice (22Rv1, MDA PCa 2b, and PC-3 xenografts) without any observed toxicities. gDEC did not impact the expression of androgen receptor (AR) or AR-variant 7 (AR-V7) nor sensitize the prostate cancer cells to the anti-androgen enzalutamide in vitro. In further investigating the mechanism of cytoreduction by gDEC, a PCR array analyses of 84 chromatin modifying enzymes demonstrated upregulation of several lysine-specific methyltransferases (KMTs: KMT2A, KMT2C, KMT2E, KMT2H, KMT5A), confirmed by additional expression analyses in vitro and of harvested xenografts. Moreover, gDEC treatment increased global histone 3 lysine 4 mono-and di-methylation (H3K4me1 and H3K4me2). In sum, gDEC, in addition to directly depleting the corepressor DNMT1, upregulated KMT activating epigenetic enzymes, activating terminal epithelial program activation, and prostate cancer cell cycling exits independent of apoptosis.

Targeting SMYD2 inhibits prostate cancer cell growth by regulating c-Myc signaling.

SMYD2 is a lysine histone methyl transferase involved in various cancers epigenetically via methylating histone H3K4, and H3K36. c-Myc is one of the major drivers ofprostate cancer (PCa) initiation and progression. The roles of SMYD2 in PCa and the regulators of c-Myc activity in PCa are still under-researched.SMYD2 expression and survival outcomes in PCa cohorts were analyzed by bioinformatics analysis. SMYD2 protein levels were detected in PCa tissues by immunohistochemistry. SMYD2 knockdown cells were established to identify the effects of SMYD2 on cell growth in vitro and in vivo. GSEA and RNA sequencing were adopted to reconnoiter the signaling regulated by SMYD2 in PCa. The relationship between SMYD2 and c-Myc was examined by western blot analysis, qPCR, and immunohistochemistry. SMYD2 specific inhibitor-AZ505 was used to pharmacologically inhibit SMYD2 function in vitro and in vivo.SMYD2 expression increased in PCa tissues compared with benign prostate tissues and higher SMYD2 expression was associated with a higher risk of biochemical relapse after radical prostatectomy. SMYD2 knockdown inhibited the growth of PCa cells both in vitro and in vivo. Furthermore, high SMYD2 levels conduced to activated c-Myc signaling in PCa cells. Importantly, the pharmacological intervention of SMYD2 by AZ505 significantly repressed PCa cell growth both in vitro and in vivo. Our findings indicate that SMYD2 inhibition restrains PCa cell proliferation by regulating c-Myc signaling and provide evidence for the potential practice of SMYD2 targeting in the treatment of PCa.

Skeletonema marinoi Extracts and Associated Carotenoid Fucoxanthin Downregulate Pro-Angiogenic Mediators on Prostate Cancer and Endothelial Cells.

The exploration of natural preventive molecules for nutraceutical and pharmaceutical use has recently increased. In this scenario, marine microorganisms represent an underestimated source of bioactive products endowed with beneficial effects on health that include anti-oxidant, anti-inflammatory, differentiating, anti-tumor, and anti-angiogenic activities. Here, we tested the potential chemopreventive and anti-angiogenic activities of an extract from the marine coastal diatom Skeletonema marinoi Sarno and Zingone (Sm) on prostate cancer (PCa) and endothelial cells. We also tested one of the main carotenoids of the diatom, the xanthophyll pigment fucoxanthin (Fuco). Fuco from the literature is a potential candidate compound involved in chemopreventive activities. Sm extract and Fuco were able to inhibit PCa cell growth and hinder vascular network formation of endothelial cells. The reduced number of cells was partially due to growth inhibition and apoptosis. We studied the molecular targets by qPCR and membrane antibody arrays. Angiogenesis and inflammation molecules were modulated. In particular, Fuco downregulated the expression of Angiopoietin 2, CXCL5, TGFβ, IL6, STAT3, MMP1, TIMP1 and TIMP2 in both prostate and endothelial cells. Our study confirmed microalgae-derived drugs as potentially relevant sources of novel nutraceuticals, providing candidates for potential dietary or dietary supplement intervention in cancer prevention approaches.

ALKBH5 Inhibits Cancer Cell Proliferation in Prostate Cancer through KLF4/TERT Signaling

N6-methyladenosine (m6A), as a reversible chemical modification of RNA, is a new type of posttranscriptional gene regulation, which plays an important role in cell differentiation and tumorigenesis, and is also a research hotspot in epigenetic transcriptomics in recent years. The purpose of this study was to discuss the action mechanism of m6A demethylase ALKBH5 in the occurrence of prostate cancer (PCa). We found that ALKBH5 was lowly expressed in PCa, and the decreased expression of ALKBH5 was responsible for the poor prognosis of prostate carcinomas. Moreover, ALKBH5 downregulated the expression of Krüppel-like factor 4 (KLF4) by reducing its mRNA stability, which reduced the transcriptional activity of KLF4 on the downstream target telomerase reverse transcriptase (TERT) and decreased TERT expression and telomerase activity, eventually inhibiting PCa cell growth. The findings of this study reveal the action mechanism of ALKBH5 in PCa from the perspective of epitranscriptomics, which would provide new ideas for the prevention of PCa.

Alisma orientale extract inhibits cell proliferation by promoting oxidative stress and apoptosis in prostate cancer cells

Prostate cancer is a prevalent malignancy in men, necessitating the development of more effective treatment drugs. Alisma is commonly used in clinical settings for various ailments, including tumors. However, its mechanism of action in prostate cancer cells remains unclear. This study aimed to clarify the effects of Alisma orientale extract (AOE) on prostate cancer. Our results showed that AOE inhibited prostate cancer cell growth and induced apoptosis while promoting oxidative stress. Mechanistically, AOE modulated the p38/nuclear factor kappa-B (NF-κB) pathway to inhibit prostate cancer progression. Taken together, these findings suggest that AOE could serve as a potential treatment for prostate cancer.

Sustained release of alpha-methylacyl-CoA racemase (AMACR) antibody-conjugated and free doxorubicin from silica nanoparticles for prostate cancer cell growth inhibition.

This article presents silica nanoparticles for the sustained release of AMACR antibody-conjugated and free doxorubicin (DOX) for the inhibition of prostate cancer cell growth. Inorganic MCM-41 silica nanoparticles were synthesized, functionalized with phenylboronic acid groups (MCM-B), and capped with dextran (MCM-B-D). The nanoparticles were then characterized using Fourier-transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, zeta potential analysis, nitrogen sorption, X-ray diffraction, and thermogravimetric analysis, before exploring their potential for drug loading and controlled drug release. This was done using a model prostate cancer drug, DOX, and a targeted prostate cancer drug, α-Methyl Acyl-CoA racemase (AMACR) antibody-conjugated DOX, which attaches specifically to AMACR proteins that are overexpressed on the surfaces of prostate cancer cells. The kinetics of sustained drug release over 30 days was then studied using zeroth order, first order, second order, Higuchi, and the Korsmeyer-Peppas models, while the thermodynamics of drug release was elucidated by determining the entropy and enthalpy changes. The flux of the released DOX was also simulated using the COMSOL Multiphysics software package. Generally, the AMACR antibody-conjugated DOX drug-loaded nanoparticles were more effective than the free DOX drug-loaded formulations in inhibiting the growth of prostate cancer cells in vitro over a 96 h period. The implications of the results are then discussed for the development of drug-eluting structures for the localized and targeted treatment of prostate cancer.

Knockdown of USP8 inhibits prostate cancer cell growth, proliferation, and metastasis and promotes docetaxel's activity by suppressing the NF-kB signaling pathway.

Ubiquitin-specific protease 8 (USP8) has been recently reported to be involved in tumorigenesis. Prostate cancer (PCa) is the most diagnosed malignancy among men, but USP8's role in PCa is not yet investigated comprehensively. Therefore, the PCa cell lines DU145 and PC3 were transfected with USP8 siRNA or overexpressing vector together with or without docetaxel. The silencing USP8 and docetaxel treatment reduced cell viability and migration and promoted apoptosis. In contrast, USP8 knockdown was found to enhance docetaxel antitumor activity. In contrast, increased cell viability and migration were noticed upon USP8 overexpression, thereby decreasing apoptosis and suppressing docetaxel antitumor activity. Notably, although EGFR, PI3K, and NF-kB were found to be increased in both USP8 overexpression and docetaxel treatment, it significantly attenuated the effects in USP8 silencing followed by with or without docetaxel. Although EGFR silencing decreased PI3K and NF-kB activation, overexpression of USP8 was shown to counteract SiEGFR's effects on NF-kB signaling by increasing PI3K expression. Our findings revealed that USP8 plays an oncogenic role in PCa and can suppress docetaxel activity. Additionally, as EGFR/PI3K/NF-kB was previously reported to develop docetaxel resistance, the combination treatment of USP8 knockdown with docetaxel might be a potential PCa therapeutic.

Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models.

Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta-analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta-analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta-analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.

Long Non-Coding RNA AC008972.1 as a Novel Therapeutic Target for Prostate Cancer.

Background: Prostate cancer is a common male malignancy and the leading cause of cancer death in men. Long non-coding RNAs (lncRNAs), microRNA (miRNAs) and mRNAs networks mediate prostate cancer progression. Herein, we investigated the functions of lncRNA AC008972.1 and its regulatory mechanism in prostate cancer. Materials and Methods: The expression levels of lncRNA AC008972.1, miR-143-3p, and TAOK2 were detected in prostate cancer tissues and cell lines by reverse transcription-quantitative polymerase chain reaction. PC3 and LNCaP cells were used to establish lncRNA AC008972.1-knockdown, miR-143-3p-overexpressing, and thousand-and-one-amino acid 2 kinase (TAOK2)-downregulated cells. Cell viability was examined by MTT assays and cell proliferation was detected by clone formation assay. Cell migration and invasion were detected by wound scratch assay and transwell chamber assay. The apoptosis rate was analyzed by flow cytometry. The protein expression was detected by Western blot assay. The RNA interaction was explored and validated by RNA binding protein immunoprecipitation (RIP) assay and dual luciferase activity assay. A mouse xenograft model was established to investigate the effect of lncRNA AC008972.1 on prostate cancer progression. Results: High expression of lncRNA AC008972.1 was associated with low overall survival in prostate cancer patients. Downregulation of lncRNA AC008972.1 suppressed prostate cancer progression by inhibiting cell viability, proliferation, migration, and invasion, in addition to the EMT process, whereas cell apoptosis was significantly promoted. LncRNA AC008972.1 bound with miR-143-3p and negatively regulated miR-143-3p expression. MiR-143-3p overexpression suppressed prostate cancer malignant behaviors in vitro. TAOK2 expression was decreased by miR-143-3p through the complementary targeting of TAOK2 mRNA. Downregulation of lncRNA AC008972.1 mitigated prostate cancer malignant behaviors in vitro based on miR-143-3p/TAOK2 node. Furthermore, the data of xenograft model experiment showed that inhibition of lncRNA AC008972.1 suppressed tumor growth in vivo. Conclusions: Knockdown of lncRNA AC008972.1 inhibits prostate cancer cell growth via downregulation of TAOK2 induced by miR-143-3p. LncRNA AC008972.1 acts as an oncogene in the progression of prostate cancer and may provide a novel therapeutic target for prostate cancer.

Abstract 3331: Effective multitargeted kinase inhibitors for metastatic castration-resistant prostate cancer predicted by integrative systems-based modeling

Abstract Metastatic castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer (PCa) with limited therapeutic opportunities. Here, we applied an unbiased systems-based modeling approach called Kinome Regularization (KiR) to identify candidate kinase inhibitors (KIs) for the treatment of CRPC. KiR is a method of target deconvolution that harnesses the polypharmacology of KIs to identify critical kinases involved in a specific cellular activity (i.e., cell proliferation). By computationally integrating the results of a functional drug screen with prior biochemical knowledge, we generated KiR models for a panel of PCa cell lines that predict KIs effective at abrogating CRPC cell growth and proliferation. Two predicted KIs (PP121 and SC-1) showed significant inhibition of PCa cell growth and kinase-mediated growth factor signaling in vitro and in primary subcutaneous tumors. However, therapy resistance emerged in bone metastases, as identified by analysis in a 3D in vitro engineered bone mimetic environment and in tumors implanted in mouse bones. A combination of PP121 and SC-1 with standard-of-care chemotherapy overcame the resistance, enhancing both tumor response and mouse survival. These results suggest that combining multi-targeted KIs with chemotherapy may represent an effective strategy for CRPC treatment. Overall, our findings demonstrate the application of a multidisciplinary strategy that blends bench science with machine-learning approaches for rapidly identifying KIs that result in desired phenotypic effects. Citation Format: Thomas Bello, Claudia Paindelli, Luis Diaz-Gomez, Antonios Mikos, Peter Nelson, Taranjit Gujral, Eleonora Dondossola. Effective multitargeted kinase inhibitors for metastatic castration-resistant prostate cancer predicted by integrative systems-based modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3331.

Novel insights into the anti-cancer effects of 3-bromopyruvic acid against castration-resistant prostate cancer

3-bromopyruvic acid (3-BP), a small molecule alkylating agent, has been emerged as a glycolytic inhibitor with anticancer activities. However, the effects of 3-BP on the growth and metastasis in prostate cancer have not been well investigated. Here we investigated the anti-cancer effects of 3-BP on prostate cancer in vitro and in vivo. Cell growth, apoptosis, migration, motility, and invasion were examined. The tumor growth ability was determined using a xenograft murine model. Transcriptome analysis using RNA-seq was performed to explore the mechanism of action of 3-BP. Our experimental results showed that 3-BP effectively inhibits prostate cancer cell growth, especially in castration-resistant prostate cancer (CRPC) cells. Moreover, 3-BP induces apoptosis and suppresses cell migration, motility, epithelial-mesenchymal transition (EMT), and invasion in CRPC cells. In addition, 3-BP also attenuates tumor growth in a xenograft murine model. Through transcriptome analysis using RNA-seq, 3-BP significantly regulates the cell cycle pathway and decreases the expression of downstream cycle cycle-associated genes in CRPC cells. The results of cell cycle analysis indicated that 3-BP arrests cell cycle progression at G2/M in CRPC cells. These results suggest that 3-BP has the potential in inhibiting CRPC progression and might be a promising drug for CRPC treatment.