Casodex treatment induces hypoxia-related gene expression in the LNCaP prostate cancer progression model

Rothermund, Christy A; Gopalakrishnan, Vishrawas; Eudy, James D.; Vishwanatha, Jamboor K.

doi:10.1186/1471-2490-5-5

Cited by 19 publications

(9 citation statements)

References 43 publications

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“…We hypothesised that some of the differences seen between the metastatic and localised cohorts were as a result of androgen regulation of the identified genes. This was investigated using published ChIP-seq data, which showed strong AR binding to the FAM129A and MME loci in multiple cell lines consistent with previous reports of altered regulation of FAM129A in cells treated with the anti-androgen, bicalutamide (Rothermund et al 2005, Wang et al 2009, Yu et al 2010, Massie et al 2011. This also suggests that MME and FAM129A are novel androgen-regulated genes, and this was confirmed by demonstrating enrichment of AR binding to the MME, FAM129A and KRT7 promoters following treatment with androgen ( Fig.…”

Section: Discussionsupporting

confidence: 81%

Whole blood mRNA in prostate cancer reveals a four-gene androgen regulated panel

Thomas

Kay²,

Menon

et al. 2016

Endocrine-Related Cancer

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Due to increased sensitivity, the expression of circulating nucleotides is rapidly gaining popularity in cancer diagnosis. Whole blood mRNA has been used in studies on a number of cancers, most notably two separate studies that used whole blood mRNA to define non-overlapping signatures of prostate cancer that has become castration independent. Prostate cancer is known to rely on androgens for initial growth, and there is increasing evidence on the importance of the androgen axis in advanced disease. Using whole blood mRNA samples from patients with prostate cancer, we have identified the four-gene panel of FAM129A, MME, KRT7 and SOD2 in circulating mRNA that are differentially expressed in a discovery cohort of metastatic samples. Validation of these genes at the mRNA and protein level was undertaken in additional cohorts defined by risk of relapse following surgery and hormone status. All the four genes were downregulated at the mRNA level in the circulation and in primary tissue, but this was not always reflected in tissue protein expression. MME demonstrated significant differences in the hormone cohorts, whereas FAM129A is downregulated at the mRNA level but is raised at the protein level in tumours. Using published ChIP-seq data, we have demonstrated that this may be due to AR binding at the FAM129A and MME loci in multiple cell lines. These data suggest that whole blood mRNA of androgen-regulated genes has the potential to be used for diagnosis and monitoring of prostate cancer.

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Section: Discussionsupporting

confidence: 81%

Whole blood mRNA in prostate cancer reveals a four-gene androgen regulated panel

Thomas

Kay²,

Menon

et al. 2016

Endocrine-Related Cancer

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“…Importantly, androgen ablation by castration induces hypoxia caused by reduced blood flow to the prostate tissue [ 43 , 44 ]. Similarly, anti-androgen casodex treatment increased the expression of hypoxia signature genes in LNCaP cells [ 45 ]. Mitani et al reported that hypoxia enhances AR transcriptional activity under low androgen conditions, mimicking the androgen independence stage [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation

et al. 2015

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Hypoxia is an independent prognostic indicator of poor outcome in several malignancies. However, precise mechanism through which hypoxia promotes disease aggressiveness is still unclear. Here, we report that under hypoxia (1% O2), human prostate cancer (PCA) cells, and extracellular vesicles (EVs) released by these cells, are significantly enriched in triglycerides due to the activation of lipogenesis-related enzymes and signaling molecules. This is likely a survival response to hypoxic stress as accumulated lipids could support growth following reoxygenation. Consistent with this, significantly higher proliferation was observed in hypoxic PCA cells following reoxygenation associated with rapid use of accumulated lipids. Importantly, lipid utilization inhibition by CPT1 inhibitor etomoxir and shRNA-mediated CPT1-knockdown significantly compromised hypoxic PCA cell proliferation following reoxygenation. Furthermore, COX2 inhibitor celecoxib strongly reduced growth and invasiveness following hypoxic PCA cells reoxygenation, and inhibited invasiveness induced by hypoxic PCA EVs. This establishes a role for COX2 enzymatic products in the enhanced PCA growth and invasiveness. Importantly, concentration and loading of EVs secreted by PCA cells were significantly compromised under delipidized serum condition and by lipogenesis inhibitors (fatostatin and silibinin). Overall, present study highlights the biological significance of lipid accumulation in hypoxic PCA cells and its therapeutic relevance in PCA.

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“…For example, the multidrug resistance 1 gene has been observed to be hypoxia-respon- sive and is regulated by HIF-1␣ (30). Treatment of LNCaP cells with the androgen receptor antagonist Casodex results in up-regulation of a subset of hypoxia-related genes, including membrane metallo-endopeptidase and cyclin G2, which might be involved in development of the androgen-independent phenotype (31).…”

Section: Discussionmentioning

confidence: 99%

BCL-xL Is a Target Gene Regulated by Hypoxia-inducible Factor-1α

Chen

Huang

et al. 2009

Journal of Biological Chemistry

154

141

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The transcription factor hypoxia-inducible factor-1␣ (HIF-1␣) plays pivotal roles in physiology and pathophysiology. Constitutive or hypoxia-induced HIF-1␣ overexpression is observed in many types of cancers including prostate adenocarcinoma, in which it is associated with resistance to apoptosis and therapeutic agents. BCL-xL, a hypoxia-responsive, anti-apoptotic protein of the Bcl-2 family, is also overexpressed in prostate carcinoma and many other cancers. Despite this connection, whether BCL-xL expression is directly regulated by HIF-1␣ is not known. We used prostate cancer PC-3 cell with constitutive high HIF-1␣ level as a model to address this important question. We first generated prostate cancer PC-3 cells in which HIF-1␣ was stably knocked-down (HIF-KD) by using small interference RNA. BCL-xL was dramatically decreased in HIF-KD PC-3 cells, in parallel with sensitization to apoptosis with caspase-3 activation as well as decreased cell proliferation. We then demonstrated that HIF-1␣ directly regulated BCL-xL transcription by binding to a hypoxia-responsive element in the BCL-xL promoter (؊865 to ؊847) by reporter gene assay, chromatin immunoprecipitation, and electrophoretic mobility shift and supershift assays. HIF-1␣-dependent BCL-xL overexpression may be an important mechanism by which HIF-1␣ protects prostate cancer cells from apoptosis and leads to treatment resistance.

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Casodex treatment induces hypoxia-related gene expression in the LNCaP prostate cancer progression model

Abstract: Background: The changes in gene expression profile as prostate cancer progresses from an androgen-dependent disease to an androgen-independent disease are still largely unknown.

Cited by 19 publications

References 43 publications

Whole blood mRNA in prostate cancer reveals a four-gene androgen regulated panel

Whole blood mRNA in prostate cancer reveals a four-gene androgen regulated panel

Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation

BCL-xL Is a Target Gene Regulated by Hypoxia-inducible Factor-1α

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