RESUMO
Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality for advanced disease states, but it often leads to the development of resistance. Enzalutamide (Enz), a second-generation antiandrogen drug, initially offers substantial therapeutic benefit, but its efficacy wanes as drug resistance ensues. In this study, we found that synaptotagmin 4 (SYT4) is an upregulated gene in enzalutamide-resistant (EnzR) cell lines. The downregulation of SYT4, in combination with enzalutamide therapy, substantially enhances the antiproliferative effect on resistant prostate cancer cells beyond the capacity of enzalutamide monotherapy. SYT4 promotes vesicle efflux by binding to the synaptosome-associated protein 25 (SNAP25), thereby contributing to cell resistance against enzalutamide. The elevated expression of SYT4 is mediated by bromodomain-containing protein 4 (BRD4), and BRD4 inhibition effectively suppressed the expression of SYT4. Treatment with a therapeutic dose of enzalutamide combined with ASO-1, an antisense oligonucleotide drug targeting SYT4, shows promising results in reversing the resistance of prostate cancer to enzalutamide.
Assuntos
Benzamidas , Resistencia a Medicamentos Antineoplásicos , Exossomos , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Sinaptotagminas , Feniltioidantoína/farmacologia , Masculino , Humanos , Linhagem Celular Tumoral , Exossomos/metabolismo , Exossomos/efeitos dos fármacos , Sinaptotagminas/metabolismo , Sinaptotagminas/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Animais , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Camundongos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas que Contêm Bromodomínio , Proteína 25 Associada a SinaptossomaRESUMO
BACKGROUND: Proteasome 26S subunit, non-ATPase 7 (PSMD7) is a deubiquitinating enzyme that is involved in the stability of ubiquitinated proteins and participates in the development of multiple types of cancer. The roles of PSMD7 and its potential mechanisms in bladder cancer (BC) remain elusive. METHODS: In this study, we identified that PSMD7 was overexpressed in BC tissues based on gene expression omnibus (GEO) database and TNMplot web. To investigate the functional role of PSMD7, two BC cell lines, T24 and 5637, were selected. The cells were transfected with vectors containing short hairpin RNAs against PSMD7 or plasmids containing full-length PSMD7 to knockdown or overexpress PSMD7. RESULTS: Our results revealed that silencing PSMD7 inhibited cell proliferation, cycle progression, migration, invasion, and promoted cell apoptosis, whereas PSMD7 overexpression led to the opposite effects in the BC cells. Mechanically, PSMD7 influenced the protein expression but not the mRNA expression of the Ras-related protein Rab-1 A (RAB1A). PSMD7 combined with RAB1A and negatively regulated its ubiquitination, indicating that PSMD7 enhanced the stability of RAB1A through post-transcriptional modification. Moreover, the rescue experiment demonstrated that RAB1A was an important downstream effector molecule of PSMD7. Besides, the negative regulation of silencing PSMD7 on tumor growth was confirmed in mice. CONCLUSIONS: Our study substantiated a novel mechanism by which PSMD7 stabilized RAB1A to accelerate the progression of BC.
Assuntos
MicroRNAs , Neoplasias da Bexiga Urinária , Animais , Camundongos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Enzimas Desubiquitinantes/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Interferente Pequeno , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , HumanosRESUMO
BACKGROUND: As a novel necrosis manner, ferroptosis has been increasingly reported to play a role in tumor progression and treatment, however, the specific mechanisms underlying its development in prostate cancer remain unclear. Growing evidence showed that peroxisome plays a key role in ferroptosis. Herein, we identified a novel mechanism for the involvement of ferroptosis in prostate cancer progression, which may provide a new strategy for clinical treatment of prostate cancer. METHODS: Label-Free Mass spectrometry was used to screen and identify candidate proteins after ferroptosis inducer-ML210 treatment. Immunohistochemistry was undertaken to explore the protein expression of AGPS in prostate cancer tissues compared with normal tissues. Co-immunoprecipitation and GST pull-down were used to identify the directly binding of AGPS to MDM2 in vivo and in vitro. CCK8 assay and colony formation assay were used to illustrate the key role of AGPS in the progression of prostate cancer in vitro. The xenograft model was established to verify the key role of AGPS in the progression of prostate cancer in vivo. RESULTS: AGPS protein expression was downregulated in prostate cancer tissues compared with normal tissues from the first affiliated hospital of Zhengzhou University dataset. Lower expression was correlated with poorer overall survival of patients compared to those with high expression of AGPS. In addition, AGPS can promote ferroptosis by modulating the function of peroxisome-resulting in the lower survival of prostate cancer cells. Furthermore, it was shown that AGPS can be ubiquitinated and degraded by the E3 ligase-MDM2 through the proteasomal pathway. Meanwhile, kinase TrkA can promote the combination of AGPS and MDM2 by phosphorylating AGPS at Y451 site. It was verified that kinase TrkA inhibitor-Larotrectinib can increase the susceptibility of prostate cancer cells to ferroptosis, which leads to the inhibition of prostate cancer proliferation to a great extent in vitro and in vivo. CONCLUSION: Based on these findings, we proposed the combination of ferroptosis inducer and TrkA inhibitor to synergistically exert anti-tumor effects, which may provide a new strategy for the clinical treatment of prostate cancer.
Assuntos
Neoplasias da Próstata , Humanos , Masculino , Próstata , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Receptores Proteína Tirosina Quinases , Ubiquitina , UbiquitinaçãoRESUMO
Cuproptosis is a new Cu-dependent programmed cell death manner that has shown regulatory functions in many tumor types, however, its mechanism in bladder cancer remains unclear. Here, we reveal that Phosphodiesterase 3B (PDE3B), a cuproptosis-associated gene, could reduce the invasion and migration of bladder cancer. PDE3B is downregulated in bladder cancer tissues, which is correlated with better prognosis. Conversely, overexpression of PDE3B in bladder cancer cell could significantly resist invasion and migration, which is consistent with the TCGA database results. Future study demonstrate the anti-cancer effect of PDE3B is mediated by Keratin 6B (KRT6B) which leads to the keratinization. Therefore, PDE3B can reduce KRT6B expression and inhibit the invasion and migration of bladder cancer. Meanwhile, increased expression of PDE3B was able to enhance the sensitivity of Cuproptosis drug thiram. This study show that PDE3B/KRT6B is a potential cancer therapeutic target and PDE3B activation is able to increase the sensitivity of bladder cancer cells to copper ionophores.
Assuntos
Movimento Celular , Cobre , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3 , Queratina-6 , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Linhagem Celular Tumoral , Cobre/metabolismo , Movimento Celular/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Queratina-6/metabolismo , Queratina-6/genética , Invasividade Neoplásica , Regulação Neoplásica da Expressão GênicaRESUMO
Sharply increased reactive oxygen species (ROS) are thought to induce oxidative stress, damage cell structure and cause cell death; however, its role in prostate cancer remains unclear. Enzalutamide is a widely used anti-prostate cancer drug that antagonizes androgen binding with its receptor. Further exploration of the mechanism and potential application strategies of enzalutamide is crucial for the treatment of prostate cancer. Here, we confirmed PEX10 can be induced by ROS activators while reduce ROS level in prostate cancer cells, which weakened the anti-tumor effect of ROS activators. The androgen receptor (AR) can promote the expression of PEX10 by acting as an enhancer in cooperation with FOXA1. The anti-tumor drug enzalutamide inhibits PEX10 by inhibiting the function of AR, and synergize with ROS activators ML210 or RSL3 to produce a stronger anti-tumor effect, thereby sensitizing cells to ROS activators. This study reveals a previously unrecognized function of enzalutamide and AR by regulating PEX10 and suggests a new strategy of enzalutamide application in prostate cancer treatment.
Assuntos
Benzamidas , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Espécies Reativas de Oxigênio , Humanos , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Masculino , Benzamidas/farmacologia , Nitrilas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Linhagem Celular Tumoral , Receptores Androgênicos/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Animais , Camundongos , Proteínas de Membrana/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos NusRESUMO
Heat shock protein family B [small] member 6 (HSPB6), widely found in various muscles, has been recently identified as a tumor suppressor gene. However, its role in prostate cancer remains unexplored. Herein, we investigated the expression of HSPB6 in prostate cancer and its association with prognosis. Our findings revealed that HSPB6 downregulation in prostate cancer correlated with a poor prognosis. Moreover, we discovered that HSPB6 can be phosphorylated and activated by 8-Br-cGMP, leading to apoptosis in prostate cancer cells by activating Cofilin. Additionally, we demonstrated that knocking down E2F1 by quinidine administration enhances the transcriptional level of HSPB6. Furthermore, we evaluated the combination of quinidine and 8-Br-cGMP as a potential therapeutic strategy for prostate cancer. Our results revealed that the combined treatment was more effective than either treatment alone in inhibiting the growth of prostate cancer through the HSPB6 pathway, both in vitro and in vivo. Overall, our study provides compelling evidence that HSPB6 suppresses malignant behavior in prostate cancer by inducing apoptosis. The combination of quinidine and 8-Br-cGMP emerges as a promising approach for the treatment of prostate cancer.
RESUMO
Amine oxidase copper-containing 1 (AOC1) is considered an oncogene in many types of tumors. Nevertheless, there have been no investigations of AOC1 and its regulatory mechanism in prostate cancer. Here, we reveal a novel action of AOC1 and a tumor suppressor mechanism in prostate cancer. AOC1 is downregulated in prostate cancer. Abatement of AOC1 in prostate cancer tissue is positively correlated with the tumor size, lymph node metastasis, and Gleason score for prostate cancer. Conversely, high expression of AOC1 is significantly associated with reduced proliferation and migration in prostate cancer both in vitro and in vivo. We show that the anticancer effect of AOC1 is mediated by its action on spermidine which leads to the activation of reactive oxygen species and ferroptosis. AOC1 expression in prostate cancer is positively regulated by the transcription factor SOX15. Therefore, SOX15 can transcriptionally promote AOC1 expression and strengthen this effect. Targeting AOC1 and SOX15 may be promising for the treatment of prostate cancer.
Assuntos
Amina Oxidase (contendo Cobre) , Ferroptose , Neoplasias da Próstata , Proliferação de Células/genética , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fatores de Transcrição SOX/genética , Fatores de Transcrição SOX/metabolismoRESUMO
Background: Adrenocortical adenocarcinoma (ACC) is known to be a relatively uncommon malignant tumor of the adrenal gland with patients having a poor prognosis. At present, few reports are available concerning the m6A modifications of lncRNAs as well as their clinical and immunological significance in the occurrence and progression of ACC. Materials and Methods: In the present research, 21 m6A-related genes were analyzed. Both multivariate and univariate Cox regression analyses were conducted to examine the prognostic m6A-related lncRNAs. A sum of 165 m6A-related lncRNAs was obtained from The Cancer Genome Atlas (TCGA) dataset. Based on the expressions of m6A-related lncRNAs, all ACC patients were classified into distinct subgroups using the consistent clustering method. Finally, m6A-related lncRNAs that were shown to have prognostic value were utilized to develop an m6A-related lncRNA risk model, which may be employed in the prediction of prognosis and survival. Results: Using TCGA data set, 26 m6A-associated lncRNAs having putative prognostic values were identified according to their expression levels, TCGA-AAC patients were classified into two clusters with the aid of consistent clustering analysis. The correlation between the two clusters was low, in which cluster1 consisted of 42% of all ACC patients. The survival analysis showed that cluster1 was associated with an unfavorable prognosis relative to cluster2. A risk model was constructed incorporating 26 m6A-associated lncRNAs that were correlated with patient prognosis. The model was subsequently validated by univariate and multivariate Cox, receiver operating characteristic (ROC) curve, and survival analyses. We also observed that the m6A-related risk model performed well in anticipating prognoses and survival status of patients with AAC. The overall survival (OS) of the high-risk cohort, as predicted by the model, was lower as opposed to that of the low-risk cohort. Conclusion: In the present research, we developed a risk model consisting of 4 m6A-related long-noncoding RNAs (lncRNAs), which can exert independent predictive values in patients with ACC. Our findings demonstrated that these 4 m6A-related lncRNAs perform integral functions in the tumor immune microenvironment, and also revealed the possibility of using these lncRNAs to guide the development of prognostic classifications and therapy approaches for ACC patients.
RESUMO
The thymus regulates a specific microenvironment for the growth and maturation of naive T cells. Involution of immune function was an important factor during body aging. Preventing the senescence of immune organs has become a major medical issue. Resveratrol (RSV) has been proved to delay the aging of many organs including the thymus. However, the underlying mechanism remains indefinite and the dosages of RSV on thymus involution need to be further clarified. In the current study, the senescence-accelerated mice were produced using d-galactose for two months. RSV at different dosages (25, 50, 100 mg kg-1 day-1 ) was then administered. The alteration of the thymic morphological structure was observed. It showed that three dosages of RSV significantly decreased cellular senescence of the thymus and no dosage difference was detected. For cellular proliferation and apoptosis of the thymus, 50 and 25 mg/kg per day of RSV displayed the best effects on cellular proliferation and apoptosis in the thymus, respectively. Furthermore, 50 mg/kg per day of RSV increased the expression of FoxN1 both at transcription and translation levels. These findings indicated that RSV could delay thymus atrophy in a dosage-dependent pattern and FoxN1 might involve in the beneficial mechanism of RSV, which was of great significance for the enhancement of thymic health and organic immunity. PRACTICAL APPLICATIONS: Resveratrol has been proved to delay aging of many organs including of thymus. In the present study, we explored the dosage of resveratrol on thymus involution and the expression of transcription factors forkhead box protein N1 (FoxN1) in the senescenceaccelerated mice induced by D-galactose. The results indicated that resveratrol could delay thymus atrophy in a dosage-dependent pattern within a certain dose range, and higher RSV concentration may have drug toxicity, which suggests that the dosage of RSV requires attention, And FoxN1 might involve in the beneficial mechanism of resveratrol supplement, which was of great significance to explore the mechanism for the enhancement of thymus immunity.
Assuntos
Fatores de Transcrição Forkhead , Galactose , Animais , Senescência Celular , Fatores de Transcrição Forkhead/genética , Camundongos , Resveratrol/farmacologia , Linfócitos TRESUMO
Senescence-related decline of thymus affects immune function in the elderly population and contributes to the prevalence of many relevant diseases like cancer, autoimmune diseases, and other chronic diseases. In this study, we investigated the therapeutic effects of curcumin, an agent that could counter aging, and explored its optimal intake and the alteration of autoimmune regulator (Aire) after curcumin treatment in the D-galactose (D-gal)-induced accelerated aging mice. ICR mice were intraperitoneally injected with D-gal for 8 weeks to establish the accelerated aging model and given curcumin with 50, 100, and 200 mg/kg body weight per day by gavage, respectively, for 6 weeks. It indicated that the D-gal-treated mice developed structural changes in the thymi compared with the control group without D-gal and curcumin treatment. As the supplements of curcumin, it resulted in a restoration of the normal thymic anatomy with an increase of proliferating cells and a reduction of apoptotic cells in the thymi of the D-gal-induced aging model mice. Curcumin administration could also expand the expression level of Aire from mRNA level and protein level. The current study demonstrated that curcumin could ameliorate senescence-related thymus involution via upregulating Aire expression, suggesting that curcumin can rejuvenate senescence-associated alterations of thymus induced by D-gal accumulation.
Assuntos
Senescência Celular/efeitos dos fármacos , Curcumina/farmacologia , Substâncias Protetoras/farmacologia , Timo/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galactose , Camundongos Endogâmicos ICR , Timo/metabolismo , Fatores de Transcrição/genética , Proteína AIRERESUMO
Senescence is an inevitable and complicated phenomenon. Age-associated thymic involution increases the risk of infectious diseases, which results in the immunosenescence and leads to a poor immune function. d-galactose (d-gal) can cause damages that resemble accelerated aging in mice. Gallic acid (GA), as one of the natural phenolic compounds, has been demonstrated to act in antioxidant and anti-tumor effects. In this study, we explored the effects of GA in preventing the age-related thymic involution and the alterations of the forkhead box protein N1 (FoxN1) in d-gal induced accelerated aging mice. The accelerated aging mice model was established by intraperitoneal injection d-gal for eight weeks and given GA with 200, 250, 500 mg/kg body weight per day, respectively, for six weeks. It showed that the d-gal-treated mice developed structural changes in the thymi compared to normal control mice. With supplement of GA, the mice restored the normal thymic anatomy, including the thickening cortex compartment and clearer cortico-medullary junction. The d-gal-treated mice showed a severe reduction in the number of thymocytes, GA mice also displayed the increased numbers of CD4 + T cells through flow cytometric analysis. GA treatment increased the proliferative cells by BrdU incorporation assay and reduced the numbers of apoptotic cells with FITC-12-dUTP labeling (TUNEL). The expression of FoxN1 was also found increased in GA treated mice by immunohistochemistry and quantitative reverse transcriptase PCR (qRT-PCR). Taken together, our results suggested that the administration of GA opposed the involution of thymus via stimulation of FoxN1 expression and proliferation of cells in a dose-dependent manner.