RESUMO
BACKGROUND: Castration-resistant prostate cancer (CRPC) patients frequently develop neuroendocrine differentiation, with high mortality and no effective treatment. However, the regulatory mechanism that connects neuroendocrine differentiation and metabolic adaptation in response to therapeutic resistance of prostate cancer remain to be unravelled. METHODS: By unbiased cross-correlation between RNA-sequencing, database signatures, and ChIP analysis, combining in vitro cell lines and in vivo animal models, we identified that PCK1 is a pivotal regulator in therapy-induced neuroendocrine differentiation of prostate cancer through a LIF/ZBTB46-driven glucose metabolism pathway. RESULTS: Upregulation of PCK1 supports cell proliferation and reciprocally increases ZBTB46 levels to promote the expression of neuroendocrine markers that are conducive to the development of neuroendocrine characteristic CRPC. PCK1 and neuroendocrine marker expressions are regulated by the ZBTB46 transcription factor upon activation of LIF signalling. Targeting PCK1 can reduce the neuroendocrine phenotype and decrease the growth of prostate cancer cells in vitro and in vivo. CONCLUSION: Our study uncovers LIF/ZBTB46 signalling activation as a key mechanism for upregulating PCK1-driven glucose metabolism and neuroendocrine differentiation of CRPC, which may yield significant improvements in prostate cancer treatment after ADT using PCK1 inhibitors.
Assuntos
Glucose/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fator Inibidor de Leucemia/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Transcrição/genética , Regulação para Cima , Animais , Linhagem Celular Tumoral , Proliferação de Células , Retroalimentação Fisiológica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Células PC-3 , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Análise de Sequência de RNARESUMO
BACKGROUND: ETS variant gene 6 (ETV6) is a putative tumor suppressor and repressed by epidermal growth factor receptor (EGFR) signaling in prostate cancer. Since EGFR antagonists seem ineffective in castration-resistant prostate cancer (CRPC), we aim to study the role of ETV6 in the development of drug resistance. METHODS: Etv6 target gene was validated by ChIP and promoter reporter assays. Correlation of ETV6 and TWIST1 was analyzed in human clinical datasets and tissue samples. Migration, invasion, and metastasis assays were used to measure the cellular responses after perturbation of ETV6 -TWIST1 axis. Proliferation and tumor growth in xenograft model were performed to evaluate the drug sensitivities of EGFR-tyrosine kinase inhibitors (TKIs). RESULTS: ETV6 inhibits TWIST1 expression and disruption of ETV6 promotes TWIST1-dependent malignant phenotypes. Importantly, ETV6 is required to the anti-proliferation effects of EGFR-TKIs, partly due to the inhibitory function of ETV6 on TWIST1. We also found that EGFR-RAS signaling is tightly controlled by ETV6, supporting its role in TKI sensitivity. CONCLUSIONS: Our study demonstrates that disruption of ETV6 contributes to EGFR-TKI resistance, which is likely due to derepression of TWIST1 and activation of EGFR-RAS signaling. Our results implicate ETV6 as a potential marker for predicting efficacy of an EGFR-targeted anticancer approach. Combination treatment of TWIST1 inhibitors could sensitize the anti-proliferation effects of EGFR-TKIs.
Assuntos
Receptores ErbB/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína 1 Relacionada a Twist/genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca2+ sensing function and multiple Ca2+-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca2+ signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca2+ and suggest its potential as a therapeutic target.
Assuntos
Diferenciação Celular , Transição Epitelial-Mesenquimal , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Androgênios/metabolismo , Androgênios/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT-driven LIF/LIFR signaling induces brain-derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration-resistant PCa (CRPC) and a positive correlation with programmed death-ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Neoplasias da Próstata , Microambiente Tumoral , Masculino , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/imunologia , Linhagem Celular Tumoral , Microambiente Tumoral/imunologia , Transdução de Sinais/efeitos dos fármacos , Fator Inibidor de Leucemia/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Animais , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/imunologia , Diferenciação CelularRESUMO
The interaction between prostate cancer (PCa) cells and prostate stromal cells fosters an immunosuppressive tumor microenvironment (TME) that promotes tumor growth and immune evasion. However, the specific signaling pathways involved remain unclear. We identified a key mechanism involving the CXCL5/CXCR2 and LIF/LIFR pathways, which create a feedforward loop that enhances neuroendocrine differentiation (NED) in PCa cells and upregulates WNT1-inducible signaling pathway protein 1 (WISP1) in both cell types. WISP1 upregulation is essential for inducing immune checkpoints and immunosuppressive cytokines via LIF/LIFR signaling and STAT3 phosphorylation. This process leads to increased neuroendocrine markers, immune checkpoints, cell proliferation, and migration. Notably, WISP1 levels in patient sera correlate with PCa progression, suggesting its potential as a biomarker. Our findings elucidate the mechanisms by which reciprocal communication between PCa cells and stromal cells contributes to the formation of an immunosuppressive TME, driving the malignant progression of PCa and highlighting potential targets for therapeutic intervention.
RESUMO
The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.
Assuntos
Diferenciação Celular , Proteína Antagonista do Receptor de Interleucina 1 , Neoplasias da Próstata , Microambiente Tumoral , Masculino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Animais , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Macrófagos/metabolismo , Macrófagos/imunologia , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F1/genéticaRESUMO
Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Humanos , Masculino , Antagonistas de Androgênios/farmacologia , Linhagem Celular Tumoral , Proteínas de Membrana , Proteínas Mitocondriais/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Piruvato Quinase/metabolismo , Transdução de SinaisRESUMO
Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteína Proto-Oncogênica N-Myc/metabolismo , Proteínas Proto-Oncogênicas c-akt , Antagonistas de Androgênios/uso terapêutico , Interferon-alfa/uso terapêutico , Microambiente Tumoral , Linhagem Celular Tumoral , Diferenciação Celular , Receptores Androgênicos/metabolismo , Receptor Muscarínico M4/uso terapêuticoRESUMO
Neuroendocrine differentiation (NED) frequently occurs in androgen-deprivation therapy (ADT)-resistant prostate cancer (PCa) and is typically associated with metabolic pathway alterations, acquisition of lineage plasticity, and malignancy. There is no conventional therapeutic approach for PCa patients with NED pathologic features because the molecular targets are unknown. Here, we evaluated the regulatory mechanism of NED-associated metabolic reprogramming induced by ADT. We detected that the loss of the androgen-responsive transcription factor, zinc finger, and BTB domain containing 10 (ZBTB10), can activate pyruvate kinase L/R (PKLR) to enhance a NED response that is associated with glucose uptake by PCa cells. PKLR exhibits a tumor-promoting effect in PCa after ADT, but ZBTB10 can compensate for the glucose metabolism and NED capacity of PKLR through the direct transcriptional downregulation of PKLR. Targeting PKLR by drug repurposing with FDA-approved compounds can reduce the aggressiveness and NED of ADT-resistant PCa. We demonstrated that PKLR acts as a modulator to activate NED in PCa enhancement by loss of ZBTB10, thereby enabling PCa cells to mount a glycolysis response essential for therapeutic resistance. Our findings highlight the broad relation between NED and metabolic dysfunction to provide gene expression-based biomarkers for NEPC treatment.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Piruvato Quinase/metabolismo , Antagonistas de Androgênios/farmacologia , Androgênios/farmacologia , Regulação para Baixo , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Piruvato Quinase/genética , Proteínas Repressoras/metabolismoRESUMO
User authentication is a crucial service in wireless sensor networks (WSNs) that is becoming increasingly common in WSNs because wireless sensor nodes are typically deployed in an unattended environment, leaving them open to possible hostile network attack. Because wireless sensor nodes are limited in computing power, data storage and communication capabilities, any user authentication protocol must be designed to operate efficiently in a resource constrained environment. In this paper, we review several proposed WSN user authentication protocols, with a detailed review of the M.L Das protocol and a cryptanalysis of Das' protocol that shows several security weaknesses. Furthermore, this paper proposes an ECC-based user authentication protocol that resolves these weaknesses. According to our analysis of security of the ECC-based protocol, it is suitable for applications with higher security requirements. Finally, we present a comparison of security, computation, and communication costs and performances for the proposed protocols. The ECC-based protocol is shown to be suitable for higher security WSNs.
Assuntos
Redes de Comunicação de Computadores/instrumentação , Segurança Computacional/instrumentação , Tecnologia sem Fio/instrumentaçãoRESUMO
Prostate cancer (PCa) is one of the most common cancers in the world and causes thousands of deaths every year. Conventional therapy for PCa includes surgery and androgen deprivation therapy (ADT). However, about 10-20% of all PCa cases relapse; there is also the further development of castration resistant adenocarcinoma (CRPC-Adeno) or neuroendocrine (NE) PCa (CRPC-NE). Due to their androgen-insensitive properties, both CRPC-Adeno and CRPC-NE have limited therapeutic options. Accordingly, this study reveals the inductive mechanisms of CRPC (for both CRPC-Adeno and CRPC-NE) and fulfils an urgent need for the treatment of PCa patients. Although previous studies have illustrated the emerging roles of epidermal growth factor receptors (EGFR), signal transducer, and activator of transcription 3 (STAT3) signaling in the development of CRPC, the regulatory mechanisms of this interaction between EGFR and STAT3 is still unclear. Our recent studies have shown that crosstalk between EGFR and STAT3 is critical for NE differentiation of PCa. In this review, we have collected recent findings with regard to the involvement of EGFR and STAT3 in malignancy progression and discussed their interactions during the development of therapeutic resistance for PCa.
RESUMO
Neuroendocrine differentiation (NED) is associated with WNT signaling activation and can be significantly observed after failure of androgen-deprivation therapy (ADT) for prostatic adenocarcinomas. Cytokine signaling is stimulated in NED prostate cancer; however, how ADT-upregulated WNT signaling promotes activation of cytokine signaling and contributes to NED of prostate cancer is poorly understood. In this study, we identified ADT-mediated upregulation of transcription factor 7 like 1 (TCF7L1), which increases the cytokine response and enhances NED of prostate cancer through interleukin (IL)-8/C-X-C motif chemokine receptor type 2 (CXCR2) signaling activation. ADT induced the secretion of WNT4 which upon engagement of TCF7L1 in prostate cancer cells, enhanced IL-8 and CXCR2 expressions. TCF7L1 directly binds to the regulatory sequence region of IL-8 and CXCR2 through WNT4 activation, thus upregulating IL-8/CXCR2 signaling-driven NED and cell motility. Analysis of prostate tissue samples collected from small-cell neuroendocrine prostate cancer (SCPC) and castration-resistant prostate cancer (CRPC) tumors showed an increased intensity of nuclear TCF7L1 associated with CXCR2. Our results suggest that induction of WNT4/TCF7L1 results in increased NED and malignancy in prostate cancer that is linked to dysregulation of androgen receptor signaling and activation of the IL-8/CXCR2 pathway.
RESUMO
Nerve growth factor (NGF) contributes to the progression of malignancy. However, the functional role and regulatory mechanisms of NGF in the development of neuroendocrine prostate cancer (NEPC) are unclear. Here, we show that an androgen-deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF. NGF regulates NEPC differentiation by physically interacting with a G-protein-coupled receptor, cholinergic receptor muscarinic 4 (CHRM4), after ADT. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4-mediated NEPC differentiation and AKT-MYCN signaling activation. CHRM4 stimulation was associated with ADT resistance and was significantly correlated with increased NGF in high-grade and small-cell neuroendocrine prostate cancer (SCNC) patient samples. Our results reveal a role of the NGF in the development of NEPC that is linked to ZBTB46 upregulation and CHRM4 accumulation. Our study provides evidence that the NGF-CHRM4 axis has potential to be considered as a therapeutic target to impair NEPC progression.
Assuntos
Adenocarcinoma/metabolismo , Carcinoma Neuroendócrino/etiologia , Fator de Crescimento Neural/metabolismo , Neoplasias da Próstata/metabolismo , Fatores de Transcrição/metabolismo , Adenocarcinoma/tratamento farmacológico , Antagonistas de Androgênios/efeitos adversos , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Estudos de Casos e Controles , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Células PC-3 , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Receptor Muscarínico M4/metabolismoRESUMO
Neuroendocrine (NE) differentiation is a well-recognized phenotypic change of prostate cancer after androgen deprivation therapy (ADT), and it ultimately develops into an aggressive subset of this disease. However, the contribution of signaling pathways that lead to metabolic disorders and NE differentiation of prostate cancer remains unclear. In this study, we identified that ADT induced upregulation of the succinate-CoA ligase GDP-forming beta subunit (SUCLG2), which regulates succinate metabolism and NE differentiation of prostate cancer. We demonstrated a connection that upregulation of epidermal growth factor receptor (EGFR)-leukemia inhibitory factor receptor (LIFR) signaling induced SUCLG2 expression in prostate cancer cells. The LIFR is upregulated by nuclear EGFR, which acts as a transcriptional regulator, directly binds to the LIFR promoter, and drives NE differentiation and glycolysis of prostate cancer. LIFR upregulation is associated with SUCLG2, which increased succinate synthesis and enzymatic activities of mitochondrial nucleoside diphosphate kinase (NDPK) in prostate cancer cells. Knockdown of SUCLG2 suppressed NE differentiation in cultured cells and reduced prostate tumor growth in a xenograft model. Analysis of prostate tissue samples showed increased intensity of nuclear EGFR associated with the LIFR and SUCLG2 in castration-resistant prostate cancer tumors. Our study provides a mechanism whereby ADT upregulates EGFR-LIFR signaling that activates SUCLG2, which subsequently stimulates the metabolic changes associated with NE differentiation and aggressive prostate cancer phenotype.
Assuntos
Antagonistas de Androgênios/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Tumores Neuroendócrinos/genética , Neoplasias de Próstata Resistentes à Castração/genética , Succinato-CoA Ligases/metabolismo , Antagonistas de Androgênios/uso terapêutico , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Núcleo Celular/patologia , Transdiferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/genética , Receptores ErbB/metabolismo , Técnicas de Silenciamento de Genes , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Masculino , Camundongos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Regiões Promotoras Genéticas , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Succinato-CoA Ligases/genética , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Androgen receptor (AR) targeting is an important therapeutic strategy for treating prostate cancer. Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT). The molecular basis for NE transdifferentiation after ADT remains incompletely understood. Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells. We demonstrated a molecular mechanism whereby ZBTB46 can be regulated by the androgen-responsive gene, SPDEF, and is associated with NE prostate cancer (NEPC) differentiation. In addition, ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels. Overexpression of ZBTB46 decreases the sensitivity of the combination of enzalutamide and a PTGS1 inhibitor; however, knockdown of ZBTB46 sensitizes the PTGS1 inhibitor and reduces tumor malignancy. ZBTB46 is inversely correlated with SPDEF and is increased in higher tumor grades and small-cell NE prostate cancer (SCNC) patients, which are positively associated with PTGS1. Our findings suggest that the induction of ZBTB46 results in increased PTGS1 expression, which is associated with NEPC progression and linked to the dysregulation of the AR-SPDEF pathway.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Ciclo-Oxigenase 1/metabolismo , Tumores Neuroendócrinos/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Nus , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Androgen deprivation therapy (ADT) targeting the androgen receptor (AR) is a standard therapeutic regimen for treating prostate cancer. However, most tumors progress to metastatic castration-resistant prostate cancer after ADT. We identified the type 1, 2, and 4 collagen-binding protein transforming growth factor-ß (TGFß)-induced protein (TGFBI) as an important factor in the epithelial-to-mesenchymal transition (EMT) and malignant progression of prostate cancer. In prostate cancer cell lines, AR signaling stimulated the activity of the transcription factor SPDEF, which repressed the expression of TGFBI ADT, AR antagonism, or overexpression of TGFBI inhibited the activity of SPDEF and enhanced the proliferation rates of prostate cancer cells. Knockdown of TGFBI suppressed migration and proliferation in cultured cells and reduced prostate tumor growth and brain and bone metastasis in xenograft models, extending the survival of tumor-bearing mice. Analysis of prostate tissue samples collected before and after ADT from the same patients showed that ADT reduced the nuclear abundance of SPDEF and increased the production of TGFBI. Our findings suggest that induction of TGFBI promotes prostate cancer growth and metastasis and can be caused by dysregulation or therapeutic inhibition of AR signaling.
Assuntos
Antagonistas de Androgênios/efeitos adversos , Neoplasias Ósseas/secundário , Transição Epitelial-Mesenquimal , Proteínas da Matriz Extracelular/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Neoplasias Ósseas/induzido quimicamente , Neoplasias Ósseas/metabolismo , Proteínas da Matriz Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-ets/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The SRC kinase has pivotal roles in multiple developmental processes and in tumor progression. An inverse relationship has been observed between androgen receptor (AR) activity and SRC signaling in advanced prostate cancer (PCa); however, the modulation of AR/SRC crosstalk that leads to metastatic PCa is unclear. Here, we showed that patients with high SRC levels displayed correspondingly low canonical AR gene signatures. Our results demonstrated that activated AR induced miR-203 and reduced SRC levels in PCa model systems. miR-203 directly binds to the 3' UTR of SRC and regulates the stability of SRC mRNA upon AR activation. Moreover, we found that progressive PCa cell migration and growth were associated with a decrease in AR-regulated miR-203 and an increase in SRC. Relationships among AR, miR-203, and SRC were also confirmed in clinical datasets and specimens. We suggest that the induction of SRC results in increased PCa metastasis that is linked to the dysregulation of the AR signaling pathway through the inactivation of miR-203.
Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Quinases da Família src/metabolismo , Humanos , Masculino , Neoplasias da Próstata/metabolismoRESUMO
Aberrant activation of Ras and WNT signaling are key events that have been shown to be up-regulated in prostate cancer that has metastasized to the bone. However, the regulatory mechanism of combinatorial Ras and WNT signaling in advanced prostate cancer is still unclear. TCF7, a WNT signaling-related gene, has been implicated as a critical factor in bone metastasis, and here we show that TCF7 is a direct target of miR-34a. In samples of prostate cancer patients, miR-34a levels are inversely correlated with TCF7 expression and a WNT dependent gene signature. Ectopic miR-34a expression inhibited bone metastasis and reduced cancer cell proliferation in a Ras-dependent xenograft model. We demonstrate that miR-34a can directly interfere with the gene expression of the anti-proliferative BIRC5, by targeting BIRC5 3'UTR. Importantly, BIRC5 overexpression was sufficient to reconstitute anti-apoptotic signaling in cells expressing high levels of miR-34a. In prostate cancer patients, we found that BIRC5 levels were positively correlated with a Ras signaling signature expression. Our data show that the bone metastasis and anti-apoptotic effects found in Ras signaling-activated prostate cancer cells require miR-34a deficiency, which in turn aids in cell survival by activating the WNT and anti-apoptotic signaling pathways thereby inducing TCF7 and BIRC5 expressions.