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Background Progression to a castration resistance state is the main cause of deaths in prostate cancer (PCa) patients. Androgen Receptor (AR) signaling plays the central role in progression of Castration Resistant Prostate Cancer (CRPC), therefore understanding the mechanisms of AR activation in the milieu of low androgen is critical to discover novel approach to treat CRPC. Methods Firstly, we explore the CRPC associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain and loss of function assays in vitro. Results The expression of Lnc-LBCS was lower in CRPC cells lines and tissues. LBCS downregulation was correlated with higher Gleason Score, T stage and poor prognosis of PCa patients. LBCS overexpression decreases, whereas LBCS knockdown increases, the traits of castration resistance in prostate cancer cells under androgen ablated or AR blocked condition. Moreover, knockdown of LBCS was sufficient to activate AR signaling in the absence of androgen by elevating the translation of AR protein. Mechanistically, LBCS interacted directly with hnRNPK to suppress AR translation efficiency by forming complex with hnRNPK and AR mRNA. Conclusions Lnc-LBCS functions as a novel AR translational regulator that suppresses castration resistance of prostate cancer by interacting with hnRNPK. This sheds a new insight into the regulation of CRPC by lncRNA mediated AR activation and LBCS-hnRNPK-AR axis provides a promising approach to the treatment of CRPC.

Background Progression to castration resistance is the leading cause of death in prostate cancer patients. Long non-coding RNAs (lncRNAs) have recently become a focal point in the regulation of cancer development. However, few lncRNAs associated with castration-resistant prostate cancer (CRPC) have been reported. Methods Firstly, we explore the CRPC associated lncRNAs by RNA sequencing and validated using quantitative polymerase chain reaction (qRT-PCR) and RNA fluorescence in situ hybridization (RNA-FISH). The clinical significance of FLJ was evaluated in a collected cancer cohort. Functional loss assays were performed to assess the effects of FLJ on CRPC cells both in vitro and in vivo. The regulatory mechanism of FLJ was investigated using immunohistochemistry (IHC), qRT-PCR, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) assays. Results FLJ is highly expressed in CRPC and is associated with higher stages and Gleason scores in prostate cancer. FLJ is strongly positively correlated with androgen receptor (AR), which acts as a transcription factor and directly binds to the FLJ promoter region to enhance its transcription. Knockdown of FLJ inhibits CRPC cell proliferation and increases sensitivity to castration and enzalutamide (ENZA) in vitro. Mechanistically, FLJ promotes castration resistance in prostate cancer cells by inhibiting AR nuclear import and cytoplasmic protein degradation, thereby activating the androgen-independent AR signaling pathway. Importantly, in vivo experiments showed that FLJ knockdown inhibited tumor growth and enhanced the therapeutic effect of ENZA. Conclusions This study identifies a novel regulatory mechanism by which lncRNA FLJ promotes CRPC progression. Sustained AR activation in CRPC acts as a transcription factor to upregulate FLJ expression. FLJ circumvents the traditional androgen-dependent survival mechanism by inhibiting AR nuclear entry and cytoplasmic protein degradation, thereby activating the AR signaling pathway. Targeting the FLJ-AR signaling axis may represent a novel therapeutic strategy for patients with castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival. Knockdown of HOXD-AS1 inhibited the proliferation and chemo-resistance of CRPC cells in vitro and in vivo. Furthermore, we identified several cell cycle, chemo-resistance, and castration-resistance-related genes, including PLK1, AURKA, CDC25C, FOXM1, and UBE2C, that were activated transcriptionally by HOXD-AS1. Further investigation revealed that HOXD-AS1 recruited WDR5 to directly regulate the expression of target genes by mediating histone H3 lysine 4 tri-methylation (H3K4me3). In conclusion, our findings indicate that HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance in prostate cancer by recruiting WDR5. This sheds a new insight into the regulation of CRPC by lncRNA and provides a potential approach for the treatment of CRPC. [Display omitted] Huang, Lin, and colleagues show that long noncoding RNA HOXD-AS1 is upregulated in castration-resistant prostate cancer (CRPC) and correlated with disease progression. HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance of prostate cancer cells via interacting with WDR5, which in turn activates the transcription of downstream genes.

Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.

Prostate cancer （PCa） is the second most common malignancy among men in the world. Castration-resistant prostate cancer （CRPC） is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy （ADT）. Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor （AR） signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.

Cabazitaxel (CBZ) is approved for docetaxel‐resistant castration‐resistant prostate cancer (CRPC). However, efficacy of CBZ for CRPC is limited and there are no effective treatments for CBZ‐resistant CRPC. In order to investigate the CBZ‐resistant mechanism, the establishment of a CBZ‐resistant cell line is urgently needed. We established CBZ‐resistant CRPC cell lines DU145CR and PC3CR by incubating DU145 and PC3 cells with gradually increasing concentrations of CBZ for approximately 2 years. We analyzed the gene expression profiles and cell cycle changes using microarray and flow cytometry. Pathway analysis revealed DU145CR cells had enhanced gene clusters of cell division and mitotic nuclear division. Enhancement of ERK signaling was detected in DU145CR cells. DU145CR cells had resistance to G2/M arrest induced by CBZ through ERK signaling activation. The MEK inhibitor PD184352 significantly inhibited cell proliferation of DU145CR. In contrast to DU145CR, PC3CR cells had enhancement of PI3K/AKT signaling. The PI3K/mTOR inhibitor NVP‐BEZ 235 had a significant antitumor effect in PC3CR cells. Cabazitaxel ‐resistant CRPC cells established in our laboratory had enhancement of cell cycle progression signals and resistance to G2/M arrest induced by CBZ. Enhancement of ERK signaling or PI3K/AKT signaling were detected in the cell lines, so ERK or PI3K/AKT could be therapeutic targets for CBZ‐resistant CRPC. Efficacy of cabazitaxel (CBZ) for castration‐resistant prostate cancer (CRPC) is limited and there are no effective treatments for CBZ‐resistant CRPC. Results of analysis in CBZ‐resistant CRPC cell lines show that MAPK and PI3K/AKT signaling might be therapeutic targets for CBZ‐resistant CRPC.

Background Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) poses a major challenge to therapeutic efficacy in castration-resistant prostate cancer (CRPC). Although circular RNAs (circRNAs) have emerged as critical regulators in cancer biology, their involvement in PARPi resistance remains largely uncharacterized. Objective This study aims to elucidate the molecular mechanism by which hsa_circ_0038737 modulates PARPi resistance in CRPC through post-transcriptional regulatory pathways. Methods We employed a comprehensive set of in vitro and in vivo approaches, including qRT-PCR, RNA sequencing, RNA-protein pull-down, RNA immunoprecipitation, functional assays, and xenograft/organoid models, to investigate the biological function and mechanistic role of hsa_circ_0038737 in CRPC progression and therapeutic response. Results We identified hsa_circ_0038737 as a nuclear-enriched circRNA significantly upregulated in CRPC, with expression levels correlating with poor prognosis and aggressive clinical features. Mechanistically, hsa_circ_0038737 interacts with RNA-binding protein (RBP) IGF2BP3, enhancing the stability of DNPH1 mRNA, a nucleotide sanitizer critical for DNA repair. The circRNA-RBP-mRNA regulatory axis promotes PARPi resistance by facilitating DNA damage repair capacity. Moreover, we revealed that reverse-complementary Alu elements mediate circRNA biogenesis, with HNRNPDL facilitating this process. Pharmacologic inhibition of DNPH1 effectively restored PARPi sensitivity both in vitro and in vivo. Conclusion Our findings reveal a novel hsa_circ_0038737/IGF2BP3/DNPH1 axis driving PARPi resistance in CRPC, offering promising potential biomarkers and therapeutic targets to overcome resistance and improve treatment outcomes in advanced prostate cancer.

The treatment of choice for prostate cancer is androgen deprivation (ADT) and novel hormonal agents such as Abiraterone, Enzalutamide, or Apalutamide. Initially, this therapy is highly effective, but a significant challenge arises as most patients eventually develop resistance, resulting in castration-resistant prostate cancer (CRPC). Furthermore, the sequential use of these drugs can lead to cross-resistance, diminishing their efficacy. Tumor heterogeneity plays a pivotal role in the development of resistance to different treatments. This study utilized cellular models of CRPC to assess the response to Apalutamide when it was administered as a second- or third-line treatment. Functional and genetic analyses were conducted in various CRPC cell models exposed to Apalutamide. These analyses included real-time cell monitoring assays, flow cytometry, clonogenicity assays, and RT-qPCR. CRPC cell models were capable of continued proliferation, maintained cell cycle profiles similar to those of untreated cells, and retained their clonogenic potential. Cross-resistance to Apalutamide in models of ADT, ADT plus Enzalutamide, or Abiraterone resistance did not correlate with the expression levels of AR-V7 and AR-V9 variants. Gene expression analysis of resistant prostate cancer cell lines revealed that treatment with Apalutamide induced the emergence of more aggressive phenotypes, including cancer stem cells or neuroendocrine differentiation profiles. Most CRPC cell models developed cross-resistance to Apalutamide and were able to proliferate and retain their clonogenic capability. Apalutamide resistance was not linked to the expression of AR-V7 or AR-V9 variants but was instead associated to bypass of AR signaling pathway and the emergence of more aggressive expression profiles.

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

Up to 30% of patients with metastatic castration‐resistant prostate cancer (CRPC) patients carry altered DNA damage response genes, enabling the use of poly adenosine diphosphate–ribose polymerase (PARP) inhibitors in advanced CRPC. The proto‐oncogene mesenchymal–epithelial transition (MET) is crucial in the migration, proliferation, and invasion of tumour cells. Aberrant expression of MET and its ligand hepatocyte growth factor is associated with drug resistance in cancer therapy. Here, we found that MET was highly expressed in human CRPC tissues and overexpressed in DU145 and PC3 cells in a drug concentration‐dependent manner and is closely related to sensitivity to PARP inhibitors. Combining the PARP inhibitor olaparib with the MET inhibitor crizotinib synergistically inhibited CRPC cell growth both in vivo and in vitro. Further analysis of the underlying molecular mechanism underlying the MET suppression‐induced drug sensitivity revealed that olaparib and crizotinib could together downregulate the ATM/ATR signaling pathway, inducing apoptosis by inhibiting the phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) pathway, enhancing the olaparib‐induced antitumour effect in DU145 and PC3 cells. In conclusion, we demonstrated that MET inhibition enhances sensitivity of CRPC to PARP inhibitors by suppressing the ATM/ATR and PI3K/AKT pathways and provides a novel, targeted therapy regimen for CRPC.