Search Results (65)

The androgen receptor (AR) signaling pathway is the primary driver of prostate cancer initiation and progression, including the development of castration-resistant prostate cancer (CRPC). Because current AR-targeted therapies inevitably encounter drug resistance, novel strategies to suppress AR signaling are urgently needed. Natural products represent a rich and structurally diverse source of bioactive compounds capable of targeting AR at multiple regulatory levels. This review overviews the interactions between natural products and the AR signaling axis through distinct mechanisms, including inhibition of testosterone production and 5α-reductase activity, direct antagonism of AR, and induction of AR degradation. In addition, several compounds disrupt AR nuclear translocation, downregulate AR splice variants, or suppress AR signaling indirectly through epigenetic regulation, microRNA modulation, or interference with co-regulator networks. Preclinical studies provide compelling evidence that these agents can effectively interrupt AR signaling, thereby suppressing prostate cancer growth. However, challenges remain, particularly the limited pharmacokinetic characterization, lack of in vivo validation, and scarcity of clinical studies. Future research should focus on improving bioavailability, exploring synergistic combinations with existing therapies, and advancing well-designed in vivo and clinical investigations. Collectively, these efforts may establish natural products as lead compounds to modulate AR signaling for prostate cancer prevention and treatment. Full article

BQ323636.1 (BQ) is a splice variant of NCOR2. Its overexpression is associated with endocrine therapy and chemoresistance in estrogen receptor-positive (ER+ve) breast cancer. This study investigates how BQ overexpression drives doxorubicin (DOX) resistance by enhancing androgen receptor (AR) signaling and non-homologous end joining (NHEJ). BQ overexpressed breast cancer cell lines (MCF-7, T-47D, BT-549, MDA-MB-453), showed increased AR activity (ARE-luciferase assay) and demonstrated DOX resistance (EC50 > 10-fold with DHT, p < 0.05), as assessed via cell viability, TUNEL, and comet assays. RNA-sequencing (GSE295979, GSE2048) revealed the involvement of AR signaling. BQ upregulated cell cycle-related kinase (CCRK), stabilizing KU70, a key NHEJ protein, resulting in enhanced NHEJ activity (EJ5-GFP assay, p < 0.01). Co-immunoprecipitation confirmed the interaction between CCRK and KU70, and CCRK was found to modulate the protein stability of KU70. AR inhibition with bicalutamide in BQ overexpressing cells reversed DOX resistance. Xenograft models validated AR-dependent DOX resistance. In ER+ve breast cancer patient samples, high CCRK expression correlated with DOX resistance (p = 0.002) and metastasis (p = 0.001). Kaplan–Meier analysis showed poorer overall survival (p < 0.001) and disease-specific survival (p < 0.001) in cancers with high CCRK. Cox-regression analysis showed that high CCRK was a poorer prognostic factor of overall survival (p < 0.001; RR 3.056, 95% CI 1.661, 5.621, AR (p < 0.001; RR 3.420, 95% CI 1.783, 6.562), and disease-specific survival (p < 0.001; RR 2.731, 95% CI 1.472, 5.067). The BQ-AR-CCRK-KU70 axis represents a novel mechanism of DOX resistance in ER+ve breast cancer, suggesting AR or CCRK inhibition as a potential therapeutic strategy. Full article

Background: The outgrowth of castration-resistant prostate cancer (CRPC) dictates patient morbidity and mortality. Recurrence of prostate cancer (PC) following androgen-deprivation therapy (ADT) often occurs due to constitutively active androgen receptor (AR) splice variants (AR-Vs), primarily AR-V7. Therefore, safe and effective therapies enabling the suppression of both full-length AR (AR-FL) and AR-Vs are urgently needed. The natural compound dimethyl sulfoxide (DMSO) has negligible cytotoxicity at concentrations below 5% and has anticancer potential. DMSO has been broadly used in biomedical research as a solvent for pharmaceuticals, as a cryoprotectant for cells, and as a topical treatment to suppress pain and inflammation. We investigated the effect of low-dose DMSO on AR expression, cell viability, and metastatic ability in PC cell lines expressing both AR-FL and AR-V7 (e.g., 22Rv1) and those expressing only AR-FL (e.g., C4-2B). Methods: MTT cell viability assays were performed to measure DMSO-induced cytotoxicity. Wound-healing assays were conducted to monitor the effect of DMSO on the migratory phenotype of cancer cells. Western blot analyses were performed to study the efficacy of DMSO in suppressing the protein levels of AR-FL and AR-V7, and expression of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) was measured as a possible mechanism. Results: At concentrations of 0.1–1% (v/v), DMSO treatment showed minimal cytotoxicity, whereas the highest concentration used (2.5%) showed approximately 20% cytotoxicity at 96 h. Interestingly, however, DMSO treatment at concentrations of 1.0 and 2.5% significantly inhibited the migration of PC cells. Treatment with DMSO led to a dose-dependent inhibition of both AR-FL and AR-V7. Notably, in 22Rv1 cells, DMSO potently downregulated the expression of hnRNPH1, a splicing factor often associated with AR expression and signaling. Conclusions: Our findings suggest that low concentrations of DMSO may have potential as an effective anticancer agent, both at the initial and later stages when PC cells become castration resistant. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine–niclosamide improves upon niclosamide’s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine–niclosamide in advanced HCC and in other cancers or diseases is warranted. Full article

Background: Second-generation androgen receptor signaling inhibitors are one of the main treatment options in metastatic castration-resistant prostate cancer (mCRPC). Nonetheless, a considerable proportion show limited response to treatment, which indicates the need for convenient, easily accessible predictor biomarkers, a role suited for liquid biopsy. Methods: We conducted a PRISMA-compliant systematic review of four databases (Embase, Medline, Scopus, Web of Science) to identify all studies (observational studies and clinical trials) investigating cell-free DNA, circulating tumor cells, exosomes, and circulating RNAs as prognostic markers in metastatic castration-resistant patients starting androgen receptor signaling inhibitors. We excluded studies that evaluated combination therapies, rare histological subtypes or included nonmetastatic or castrate-sensitive disease. We also evaluated whether published papers followed reporting guidelines (REMARK, STROBE, or CONSORT for abstracts). Results: We identified a total of 123 reports, from which we identified only a few well-studied and consistent biomarkers: androgen receptor overexpression/copy number gain and splice variant 7, as well as disease burden markers (circulating tumor DNA fraction and circulating tumor cell concentration). Alterations or copy number loss in tumor suppressors PTEN, RB1, and TP53 were second in terms of quantity and consistency of evidence. However, a large majority of identified biomarkers were relatively understudied or inconsistent. We identified two potential vulnerabilities: inconsistent adherence to reporting guidelines and the under-inclusion of patients of non-Western European ancestry. Conclusions: A large number of biomarkers were linked to worse outcomes in prostate cancer; nonetheless, in most cases, the evidence is limited or inconsistent, or even contradictory. The main exceptions pertain to androgen receptor signaling and disease burden, and, to a smaller extent, to certain tumor suppressor genes. Further studies are needed to confirm their clinical utility, using clear and consistent methodologies and including patients from currently understudied populations. Full article

Introduction: Prostate cancer with spinal metastases (PCSM) is associated with high morbidity and mortality. The impact of biomarkers on the prognosis of spinal metastases, however, remains unclear. Objective: This study explored associations between potential biomarkers, treatment modalities, survival, and neurological outcomes in PCSM patients. Methods: We conducted a retrospective analysis of 68 patients as part of a neurosurgical cohort with PCSM at a comprehensive cancer center from 2013 to 2023, examining the influence of potential biomarkers, treatment modalities, and demographics on prognosis. The primary outcomes were the identification of biomarkers, overall survival (OS) in years, survival after spinal metastasis in years, spinal metastasis recurrence, and postoperative neurological outcomes via Frankel scores. Results: All the patients (n = 68) had adenocarcinoma, and the median age was 69 years. The mortality rate was 66% with a median OS of 6 years. Seventy-two biomarkers were identified. An accelerated failure time model (AFT) showed that radiotherapy to the prostate increased the OS (TR = 1.805, p = 0.001), while smoking status (TR = 0.625, p < 0.001) and PTEN gene mutations (TR = 0.504, p = 0.006) were associated with decreased OS. Kaplan–Meier analysis associated PTEN mutations with reduced median OS using the Gehan–Breslow–Wilcoxon test (3.50 vs. 9.49 years; p = 0.001). PTEN mutations were trending towards but were not significant for decreased survival following spinal metastases (2.04 vs. 3.15 years; p = 0.08). Both PTEN (p = 0.02) and Tumor Protein 53 (TP53, p = 0.01) mutations were associated with increased spinal metastasis recurrence when analyzed using Fisher’s exact test. No differences were observed in the median OS or survival after spinal metastases among patients with or without androgen receptor splice variant-7 (AR-V7), prostate-specific membrane antigen (PSMA), TP53, or other analyzed biomarkers. Similarly, neither age, receipt of chemotherapy, nor radiotherapy to the spine correlated with OS. Only chemotherapy was associated with a decreased postoperative Frankel Score (p = 0.002). Conclusions: PTEN mutations and smoking status were associated with decreased OS in patients with PCSM. Both PTEN and TP53 mutations were associated with increased spinal metastasis recurrence. Receipt of radiotherapy to the prostate was correlated with prolonged survival, whereas receipt of radiotherapy to the spine was not. Chemotherapy was associated with decreased postoperative neurological outcomes. Full article

Metastatic prostate cancer (mPCa) remains a significant cause of cancer-related mortality in men. Advances in molecular profiling have demonstrated that the androgen receptor (AR) axis, DNA damage repair pathways, and the PI3K/AKT/mTOR pathway are critical drivers of disease progression and therapeutic resistance. Despite the established benefits of hormone therapy, chemotherapy, and bone-targeting agents, mPCa commonly becomes treatment-resistant. Recent breakthroughs have highlighted the importance of identifying actionable genetic alterations, such as BRCA2 or ATM defects, that render tumors sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Parallel efforts have refined imaging—particularly prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography—to detect and localize metastatic lesions with high sensitivity, thereby guiding patient selection for PSMA-targeted radioligand therapies. Multi-omics innovations, including liquid biopsy technologies, enable the real-time tracking of emergent AR splice variants or reversion mutations, supporting adaptive therapy paradigms. Nonetheless, the complexity of mPCa necessitates combination strategies, such as pairing AR inhibition with PI3K/AKT blockade or PARP inhibitors, to inhibit tumor plasticity. Immuno-oncological approaches remain challenging for unselected patients; however, subsets with mismatch repair deficiency or neuroendocrine phenotypes may benefit from immune checkpoint blockade or targeted epigenetic interventions. We present these pivotal advances, and discuss how biomarker-guided integrative treatments can improve mPCa management. Full article

Background/Objectives: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fail due to the emergent expression of AR RNA splice variants, such as AR-V7, that can signal independently of ligand binding. Other therapies, such as vaccination against prostate-specific antigens, have achieved FDA approvals but have fallen short of being incorporated as standard-of-care therapies for advanced prostate cancer. This may be due to the elevated level of immunosuppression observed in prostate cancer, which remains largely refractory to immune checkpoint blockade. Methods: We developed a vaccine targeting AR-V7, a common isoform associated with treatment resistance, and demonstrated its ability to elicit AR-V7-specific immunity and enable anti-tumor responses against AR-V7+ cancers in subcutaneous tumor models. Results: Our studies also revealed that AR-V7 expression conferred an immune suppressive phenotype that was significant in a non-AR-dependent prostate cancer model. Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. Conclusions: Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors. Full article

Castration-resistant prostate cancer (CRPC) remains a significant therapeutic challenge due to its resistance to standard androgen deprivation therapy (ADT). The emergence of androgen receptor splice variant 7 (AR-V7) has been implicated in CRPC progression, contributing to treatment resistance. Current treatments, including first-generation chemotherapy, androgen receptor blockers, radiation therapy, immune therapy, and PARP inhibitors, often come with substantial side effects and limited efficacy. Natural compounds, particularly those derived from herbal medicine, have garnered increasing interest as adjunctive therapeutic agents against CRPC. This review explores the role of AR-V7 in CRPC and highlights the promising benefits of natural compounds as complementary treatments to conventional drugs in reducing CRPC and overcoming therapeutic resistance. We delve into the mechanisms of action underlying the anti-CRPC effects of natural compounds, showcasing their potential to enhance therapeutic outcomes while mitigating the side effects associated with conventional therapies. The exploration of natural compounds offers promising avenues for developing novel treatment strategies that enhance therapeutic outcomes and reduce the adverse effects of conventional CRPC therapies. These compounds provide a safer, more effective approach to managing CRPC, representing a significant advancement in improving patient care. Full article

Latrophilins (LPHNs), a group of the G-protein–coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. We assessed the actions of LPHNs, including LPHN1, LPHN2, and LPHN3, in human prostate cancer lines via their ligand (e.g., α-LTX, FLRT3) treatment or shRNA infection, as well as in surgical specimens. In androgen receptor (AR)-positive LNCaP/C4-2/22Rv1 cells, dihydrotestosterone considerably increased the expression levels of LPHNs, while chromatin immunoprecipitation assay revealed the binding of endogenous ARs, including AR-V7, to the promoter region of each LPHN. Treatment with α-LTX or FLRT3 resulted in induction in the cell viability and migration of both AR-positive and AR-negative lines. α-LTX and FLRT3 also enhanced the expression of Bcl-2 and phosphorylated forms of JAK2 and STAT3. Meanwhile, the knockdown of each LPHN showed opposite effects on all of those mediated by ligand treatment. Immunohistochemistry in radical prostatectomy specimens further showed the significantly elevated expression of each LPHN in prostate cancer, compared with adjacent normal-appearing prostate, which was associated with a significantly higher risk of postoperative biochemical recurrence in both univariate and multivariable settings. These findings indicate that LPHNs function as downstream effectors of ARs and promote the growth of androgen-sensitive, castration-resistant, or even AR-negative prostate cancer. Full article

Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular treatment and result in resistant and aggressive disease. These breast cancers usually have fewer treatment options. Targeted therapies for cancer patients may offer fewer adverse side effects because of specificity compared to conventional chemotherapy. Signaling pathways of nuclear receptors, such as the estrogen receptor (ER), have been intensively studied and used as therapeutic targets. Recently, the role of the androgen receptor (AR) in breast cancer is gaining greater attention as a therapeutic target and as a prognostic biomarker. The expression of constitutively active truncated AR splice variants in breast cancer is a possible mechanism contributing to treatment resistance. Therefore, targeting both the full-length AR and AR variants, either through the activation or suppression of AR function, depending on the status of the ER, progesterone receptor, or human epidermal growth factor receptor 2, may provide additional treatment options. Studies targeting AR in combination with other treatment strategies are ongoing in clinical trials. The determination of the status of nuclear receptors to classify and identify patient subgroups will facilitate optimized and targeted combination therapies. Full article

The progression of prostate cancer (PCa) relies on the activation of the androgen receptor (AR) by androgens. Despite efforts to block this pathway through androgen deprivation therapy, resistance can occur through several mechanisms, including the abnormal activation of AR, resulting in castration-resistant PCa following the introduction of treatment. Mutations, amplifications, and splicing variants in AR-related genes have garnered attention in this regard. Furthermore, recent large-scale next-generation sequencing analysis has revealed the critical roles of AR and AR-related genes, as well as the DNA repair, PI3K, and cell cycle pathways, in the onset and progression of PCa. Moreover, research on epigenomics and microRNA has increasingly become popular; however, it has not translated into the development of effective therapeutic strategies. Additionally, treatments targeting homologous recombination repair mutations and the PI3K/Akt pathway have been developed and are increasingly accessible, and multiple clinical trials have investigated the efficacy of immune checkpoint inhibitors. In this comprehensive review, we outline the status of PCa research in genomics and briefly explore potential future developments in the field of epigenetic modifications and microRNAs. Full article

Therapeutic options for advanced prostate cancer have vastly expanded over the last decade and will continue to expand in the future. Drugs targeting the androgen receptor (AR) signaling pathway, i.e., androgen receptor targeting agents (ARTAs), remain the mainstream treatments that are increasingly transforming the disease into one that can be controlled for an extended period of time. Prostate cancer is inherently addicted to AR. Under the treatment pressure of ARTA, molecular alterations occur, leading to the clonal expansion of resistant cells in a disease state broadly categorized as castration-resistant prostate cancer (CRPC). One castration resistance mechanism involves AR splice variants (AR-Vs) lacking the ligand-binding domain. Some AR-Vs have been identified as constitutively active, capable of activating AR signaling pathways without androgenic ligands. Among these variants, AR-V7 is the most extensively studied and may be measured non-invasively using validated circulating tumor cell (CTC) tests. In the context of the evolving prostate cancer treatment landscape, novel agents are developed and evaluated for their efficacy in targeting AR-V7. In patients with metastatic CRPC (mCRPC), the availability of the AR-V7 tests will make it possible to determine whether the treatments are effective for CTC AR-V7-positive disease, even though the treatments may not be specifically designed to target AR-V7. In this review, we will first outline the current prostate cancer treatment landscape, followed by an in-depth review of relatively newer prostate cancer therapeutics, focusing on AR-targeting agents under clinical development. These drugs are categorized from the standpoint of their activities against AR-V7 through direct or indirect mechanisms. Full article

Multiple studies have demonstrated the importance of androgen receptor (AR) splice variants (SVs) in the progression of prostate cancer to the castration-resistant phenotype and their utility as a diagnostic. However, studies on AR expression in non-prostatic malignancies uncovered that AR-SVs are expressed in glioblastoma, breast, salivary, bladder, kidney, and liver cancers, where they have diverse roles in tumorigenesis. AR-SVs also have roles in non-cancer pathologies. In granulosa cells from women with polycystic ovarian syndrome, unique AR-SVs lead to an increase in androgen production. In patients with nonobstructive azoospermia, testicular Sertoli cells exhibit differential expression of AR-SVs, which is associated with impaired spermatogenesis. Moreover, AR-SVs have been identified in normal cells, including blood mononuclear cells, neuronal lipid rafts, and the placenta. The detection and characterization of AR-SVs in mammalian and non-mammalian species argue that AR-SV expression is evolutionarily conserved and that AR-SV-dependent signaling is a fundamental regulatory feature in multiple cellular contexts. These discoveries argue that alternative splicing of the AR transcript is a commonly used mechanism that leads to an expansion in the repertoire of signaling molecules needed in certain tissues. Various malignancies appropriate this mechanism of alternative AR splicing to acquire a proliferative and survival advantage. Full article

Androgen receptor (AR) is a viable therapeutic target for lethal castration-resistant prostate cancer (CRPC), because the continued progression of CRPC is mainly driven by the reactivation of AR transcriptional activity. The current FDA-approved AR antagonists binding to ligand binding domain (LBD) become ineffective in CRPC with AR gene amplification, LBD mutation, and the evolution of LBD-truncated AR splice variants. Encouraged by the fact that tricyclic aromatic diterpenoid QW07 has recently been established as a potential N-terminal AR antagonist, this study aims to explore the structure–activity relationship of tricyclic diterpenoids and their potential to suppress AR-positive cell proliferation. Dehydroabietylamine, abietic acid, dehydroabietic acid, and their derivatives were selected, since they have a similar core structure as QW07. Twenty diterpenoids were prepared for the evaluation of their antiproliferative potency on AR-positive prostate cancer cell models (LNCaP and 22Rv1) using AR-null cell models (PC-3 and DU145) as comparisons. Our data indicated that six tricyclic diterpenoids possess greater potency than enzalutamide (FDA-approved AR antagonist) towards LNCaP and 22Rv1 AR-positive cells, and four diterpenoids are more potent than enzalutamide against 22Rv1 AR-positive cells. The optimal derivative possesses greater potency (IC₅₀ = 0.27 µM) and selectivity than QW07 towards AR-positive 22Rv1 cells. Full article