SIRT5 is the desuccinylase of LDHA as novel cancer metastatic stimulator in aggressive prostate cancer

Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Among patients who developed advanced PCa, 80% suffered from bone metastasis, with a sharp drop in the survival rate. Despite great efforts, the details of the mechanisms underlying castration-resistant PCa (CRPC) remains unclear. SIRT5, an NAD+-dependent desuccinylase, is hypothesized to be a key regulator of various cancers. However, compared to other SIRTs, the role of SIRT5 in cancer has not been extensively studied. Here, we showed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages. The correlation between the decrease in the SIRT5 level and the patients survival rate was also confirmed. Using quantitative global succinylome analysis, we characterized a significant increase of lysine 118 succinylation (K118su) of lactate dehydrogenase A (LDHA), which plays a role in increasing LDH activity. As a substrate of SIRT5, LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients. This study investigated the reduction of SIRT5 and LDHA-K118su as a novel mechanism involved in PCa progression. It can also be proposed as a new target that can prevent castration-resistant PCa progression, which is key to PCa treatment.

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The role of microbiota in driving castration-resistant prostate cancer

10.26226/morressier.5f69edb69b74b699bf38c5cf ◽

2020 ◽

Author(s):

Arianna Calcinotto

Keyword(s):

Prostate Cancer ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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The Role of Interleukin-6/GP130 Signaling in Prostate Cancer Progression and Its Contribution to Bone Metastasis Morbidity

10.21236/ada469521 ◽

2007 ◽

Author(s):

Richard P. Redvers

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cancer Progression ◽

Interleukin 6 ◽

Prostate Cancer Progression

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AR Copy Number and AR Signaling-directed Therapies in Castrationresistant Prostate Cancer

Current Cancer Drug Targets ◽

10.2174/1568009617666171122145852 ◽

2018 ◽

Vol 18 (9) ◽

pp. 869-876

Author(s):

Samanta Salvi ◽

Vincenza Conteduca ◽

Cristian Lolli ◽

Sara Testoni ◽

Valentina Casadio ◽

...

Keyword(s):

Prostate Cancer ◽

Copy Number ◽

Clinical Trial Design ◽

Complete Information ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Anti Cancer ◽

Hormone Sensitive ◽

Predictive And Prognostic Biomarker

Background: Adaptive upregulation of Androgen Receptor (AR) is the most common event involved in the progression from hormone sensitive to Castration-Resistant Prostate Cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. Objective: In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR Copy Number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Conclusion: Outcomes of CRPC patients are reported to be highly variable as the consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design.

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Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20092066 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2066 ◽

Cited By ~ 12

Author(s):

Namrata Khurana ◽

Suresh C. Sikka

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Signaling Pathways ◽

Critical Role ◽

Castration Resistant Prostate Cancer ◽

Form Complex ◽

Androgen Receptor Signaling ◽

Castration Resistant ◽

Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

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The role of microRNA-572 in the proliferation and chemotherapeutic treatment of prostate cancer

Journal of International Medical Research ◽

10.1177/03000605211014363 ◽

2021 ◽

Vol 49 (5) ◽

pp. 030006052110143

Author(s):

Mingcui Zang ◽

Xun Guo ◽

Manqiu Chen

Keyword(s):

Prostate Cancer ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Prostate Tumorigenesis ◽

Expression Levels ◽

Matrigel Invasion ◽

Tensin Homolog ◽

Docetaxel Treatment ◽

Induced Apoptosis

Objective MicroRNAs (miRNAs) regulate prostate tumorigenesis and progression by involving different molecular pathways. In this study, we examined the role of miR-572 in prostate cancer (PCa). Methods The proliferation rates of LNCaP and PC-3 PCa cells were studied using MTT assays. Transwell migration and Matrigel invasion assays were performed to evaluate cell migration and invasion, respectively. Protein expression levels were examined using western blotting. Docetaxel-induced apoptosis was evaluated by Caspase-Glo3/7 assays. The putative miR-572 binding site in the phosphatase and tensin homolog (PTEN) 3ʹ untranslated region (3ʹ UTR) was assessed with dual-luciferase reporter assays. Additionally, miR-572 expression levels in human PCa tissues were examined by qRT-PCR assays. Results Upregulation of miR-572 promoted proliferation, migration, and invasion of PCa cells. Overexpression of miR-572 decreased sensitivity of PCa cells to docetaxel treatment by reducing docetaxel-induced apoptosis. MiR-572 can regulate migration and invasion in PCa cells. Furthermore, miR-572 could regulate expression of PTEN and p-AKT in PCa cells by directly binding to the PTEN 3ʹ UTR. MiR-572 expression levels were increased in human PCa tissues and associated with PCa stage. Conclusions miR-572 displayed essential roles in PCa tumor growth and its expression level may be used to predict docetaxel treatment in these tumors.

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Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽

10.3390/cancers13163959 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3959

Author(s):

Oluwaseun Adebayo Bamodu ◽

Yuan-Hung Wang ◽

Chen-Hsun Ho ◽

Su-Wei Hu ◽

Chia-Da Lin ◽

...

Keyword(s):

Prostate Cancer ◽

Disease Progression ◽

Therapy Resistance ◽

Calcium Signal ◽

Signal Transducer ◽

Castration Resistance ◽

Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

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