Bench-to-bedside development of agonists and antagonists of luteinizing hormone–releasing hormone for treatment of advanced prostate cancer

Rick, Ferenc G.; Schally, Andrew V.

doi:10.1016/j.urolonc.2014.11.006

Cited by 26 publications

(20 citation statements)

References 44 publications

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“…GnRH binds to a specific GnRH receptor, a member of the large superfamily of seven transmembrane domain receptors that bind to G-proteins [48, 49]. Studies revealed that GnRH receptors is expressed in breast, ovarian, endometrial and prostate_ENREF_50 cancers and that the proliferation in vitro can be repressed by agonistic or antagonistic analogs in various human cancer cell lines [50-53]. Our study found that PVT1 is involved in tumor progression by regulating the GnRH pathway.…”

Section: Discussionmentioning

confidence: 66%

Prognostic Significance of LncRNA PVT1 and Its Potential Target Gene Network in Human Cancers: a Comprehensive Inquiry Based Upon 21 Cancer Types and 9972 Cases

Qin

Lin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Whether the level of long noncoding RNA plasmacytoma variant translocation 1 gene (lncRNA PVT1) expression influences the clinical development and outcome of human cancers has not been thoroughly elucidated to date. Inconsistencies still exist regarding the associations between PVT1 and the clinicopathological features, including patient survival data. Additionally, the regulatory mechanism of PVT1 among human cancers remains unclear. Methods: we conducted a comprehensive inquiry to verify the implication of PVT1 expression in cancer patients by conducting a meta-analysis of 19 selected studies and The Cancer Genome Atlas (TCGA) database to examine the relationship between PVT1 expression and both the prognosis and clinicopathological features of cancer patients using STATA 12.0. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the potential mRNA target genes of PVT1 gathered from TANRIC and Multi Experiment Matrix (MEM) were performed. Results: The level of PVT1 expression in tumor tissues was higher than in paired non-cancer tissues and was significantly associated with a poorer prognosis in cancer patients. Additionally, overexpression of PVT1 was significantly correlated with histological differentiation, tumor (T) classification, lymph node (N) classification and TNM stages. Furthermore, a total of 462 validated target genes were identified, and the GO and KEGG analyses demonstrated that the validated targets of PVT1 were significantly enriched in several pathways, including the GnRH signaling pathway, the Cytokine-cytokine receptor interaction pathway, the Inflammatory mediator regulation of TRP channels pathway, and the Neuroactive ligand-receptor interaction pathway. Conclusion: PVT1 may serve as a potential biomarker associated with the progression and prognosis of human cancers.

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Section: Discussionmentioning

confidence: 66%

Prognostic Significance of LncRNA PVT1 and Its Potential Target Gene Network in Human Cancers: a Comprehensive Inquiry Based Upon 21 Cancer Types and 9972 Cases

Qin

Lin

et al. 2018

Cell Physiol Biochem

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“…Thus, androgen deprivation therapy (ADT) is used to treat advanced prostate and yields transient efficacy. This therapy consists in administrating LHRH agonists or antagonist which prevent the secretion of the pituitary hormone LH which, in turn, reduces the production of androgens by the testicles [ 2 ]. In addition, patients can also receive antiandrogen treatment to block the effects of adrenal residual androgens, this strategy has been termed “combined androgen blockage” [ 3 – 5 ].…”

Section: Introductionmentioning

confidence: 99%

Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells

et al. 2016

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Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE model of prostate cancer. Serum deprivation increased the expression of NE markers such as neuron-specific enolase (NSE) and βIII tubulin (βIII tub) and decreased the expression of the androgen receptor protein in LNCaP cells. Using cDNA microarrays, we compared gene expression profiles of NE cells and non-differentiated LNCaP cells. We identified up-regulation of 155 genes, among them LAMP2, a lysosomal membrane protein involved in lysosomal stability and autophagy. We then confirmed up-regulation of LAMP2 in NE cells by qRT-PCR, Western blot and confocal microscopy assays, showing that mRNA up-regulation correlated with increased levels of LAMP2 protein. Subsequently, we determined autophagy activity in NE cells by assessing the protein levels of SQSTM/p62 and LC3 by Western blot and LC3 and Atg5 mRNAs content by qRT-PCR. The decreased levels of SQSTM/p62 was accompanied by an enhanced expression of LC3 and ATG5, suggesting activation of autophagy in NE cells. Blockage of autophagy with 1μM AKT inhibitor IV, or by silencing Beclin 1 and Atg5, prevented NE cell differentiation, as revealed by decreased levels of the NE markers. In addition, AKT inhibitor IV as well as Beclin1 and Atg5 kwockdown attenuated LAMP2 expression in NE cells. On the other hand, LAMP2 knockdown by siRNA led to a marked blockage of autophagy, prevention of NE differentiation and decrease of cell survival. Taken together, these results suggest that LAMP2 overexpression assists NE differentiation of LNCaP cells induced by serum deprivation and facilitates autophagy activity in order to attain the NE phenotype and cell survival. LAMP2 could thus be a potential biomarker and potential target for NE prostate cancer.

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“…Prostate cancer is the most commonly diagnosed cancer among males in the United States, with more than 29,000 men estimated to die from this disease in 2014 1 . The critical driver of prostate tumor progression is the androgen receptor (AR), and when the cancer has progressed past definitive local therapy, therapeutic strategies that target testicular androgen production (LH-RH agonists) 2 , 3 or competitively inhibit androgen binding to the receptor (AR antagonists) are employed 4 . The suppression of AR function by anti-endocrine therapies is initially effective, but most tumors develop resistance, resulting in a more aggressive cancer known as castration-resistant prostate cancer (CRPC) 5 .…”

Section: Introductionmentioning

confidence: 99%

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

et al. 2016

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Clinical resistance to the second-generation antiandrogen enzalutamide in castration resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights the unmet medical need for next generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide), and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR:CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm bound to heat shock proteins. Thus, we have identified third generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC.

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Bench-to-bedside development of agonists and antagonists of luteinizing hormone–releasing hormone for treatment of advanced prostate cancer

Cited by 26 publications

References 44 publications

Prognostic Significance of LncRNA PVT1 and Its Potential Target Gene Network in Human Cancers: a Comprehensive Inquiry Based Upon 21 Cancer Types and 9972 Cases

Prognostic Significance of LncRNA PVT1 and Its Potential Target Gene Network in Human Cancers: a Comprehensive Inquiry Based Upon 21 Cancer Types and 9972 Cases

Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

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