Altered expression of farnesyl pyrophosphate synthase in prostate cancer: evidence for a role of the mevalonate pathway in disease progression?

2012 ◽  
Vol 31 (2) ◽  
pp. 345-350 ◽  
Author(s):  
Tilman Todenhöfer ◽  
Jörg Hennenlotter ◽  
Ursula Kühs ◽  
Valentina Gerber ◽  
Georgios Gakis ◽  
...  
Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3959
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Yuan-Hung Wang ◽  
Chen-Hsun Ho ◽  
Su-Wei Hu ◽  
Chia-Da Lin ◽  
...  

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.


2020 ◽  
Vol 77 (4) ◽  
pp. 501-507 ◽  
Author(s):  
Gregory T. Chesnut ◽  
Emily A. Vertosick ◽  
Nicole Benfante ◽  
Daniel D. Sjoberg ◽  
Jonathan Fainberg ◽  
...  

Forests ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1053
Author(s):  
Zhuo Wang ◽  
Hongyu Guo ◽  
Yantong Zhang ◽  
Limei Lin ◽  
Minghui Cui ◽  
...  

Eleutherococcus senticosus (Ruper. et Maxim.) Maxim is a traditional Chinese medicine. The saponin components of E. senticosus have several biological effects, including reduction of blood lipids; protection against liver, heart, and vascular disease; and antitumor activity. The DNA methylation of E. senticosus farnesyl pyrophosphate synthase (FPS), squalene synthase (SS), and squalene epoxidase (SE) gene promoters and the mechanism of the influence of these enzymes on saponin synthesis and accumulation in E. senticosus were explored using bisulfite sequencing technology, real-time PCR, the vanillin-concentrated sulfuric acid chromogenic method, and LC-MS. There are 19 DNA methylation sites and 8 methylation types in the FPS gene. The SS gene has nine DNA methylation sites and two DNA methylation types. The SE gene has 16 DNA methylation sites and 7 methylation types. The total saponin content in the high and low DNA methylation groups were 1.07 ± 0.12 and 2.92 ± 0.32 mg/g, respectively. Statistical analysis indicated that the gene expression of the FPS, SS, and SE genes was significantly positively correlated with the saponin content (p < 0.05), and that the methylation ratio was significantly negatively correlated with the saponin content (p < 0.01), while the expression of the SS and SE genes was significantly positively correlated (p < 0.01). A total of 488 metabolites were detected from E. senticosus and 100 different metabolites were screened out by extensive targeted metabolomics. The amount of most metabolites related to the mevalonate pathway was higher in the low DNA methylation group than in the high DNA methylation group. It was demonstrated that there are DNA methylation sites in the promoter regions of the FPS, SS, and SE genes of E. senticosus, and DNA methylation in this region could significantly inhibit synthesis in the mevalonate pathway, thus reducing the content of the final product E. senticosus saponin.


Drug Research ◽  
2018 ◽  
Vol 69 (03) ◽  
pp. 159-167 ◽  
Author(s):  
Parvin Kumar ◽  
Ashwani Kumar ◽  
Jayant Sindhu ◽  
Sohan Lal

AbstractHuman farnesyl pyrophosphate synthase (hFPPS) is a well-settled therapeutic target and it is an enzyme of the mevalonate pathway which catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate. QSAR studies by using Monte Carlo method for human farnesyl pyrophosphate synthase inhibitors has been carried out using balance of correlation technique with Index of ideality correlation. For construction of QSAR models, six random splits were prepared from the data of 73 phosphonates and hybrid optimal descriptors procured from graph (HFG) and SMILES based notations were employed. The developed QSAR models have robustness, good fitting ability, generalizability and internal predictive ability. The external predictive ability has been certified by testing various precedents. The values of R2, IIC, Q2 and ∆R2 m for the best model are 0.9304, 0.9614, 0.9061 and 0.0861 respectively. The developed QSAR models met with the specified standards given in OECD guideline and applicability domain. The structural feature promoters for the end point increase and promoters for end point decrease have been extracted. The predicted pIC50 for the new proposed compounds have also been reported.


2018 ◽  
Vol 25 (6) ◽  
pp. 1509-1511 ◽  
Author(s):  
Poorva Bindal ◽  
Sharif AA Jalil ◽  
Lisa M Holle ◽  
Jessica M Clement

Nearly all men with prostate cancer who are treated with androgen deprivation therapy develop disease progression. There is considerable evidence to suggest that CXCL 13 released by tumor cells leads to B-cell infiltration into the prostate cells. This B-cell infiltration has been postulated to play a role in development of disease progression following androgen-deprivation therapies. We present a case of a patient who achieved remission of metastatic castrate-resistant prostate cancer after receiving rituximab and bendamustine for the treatment of follicular lymphoma. The findings in this report suggest that further investigation is warranted for utilizing B-cell targeted therapy in delaying progression of castrate-resistant prostate cancer.


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