Landmarks in hormonal therapy for prostate cancer

Hammerer, Peter; Madersbacher, Stephan

doi:10.1111/j.1464-410x.2012.11431.x

Cited by 24 publications

(21 citation statements)

References 70 publications

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“…Within this dataset, there are a total of 218 cases and we selected the prostatectomy samples that later on developed into metastatic disease and compared these with the cases without prostate cancer (PAN) based on the clinical data described in Supplementary Table S1 of Taylor and colleagues (32). expression arrays and data were processed using J-Express (28) to produce lists of up-and downregulated genes from each treatment and time point (Supplementary Table S2.). We first evaluated the expression profiles after treating cells with siOGT.…”

Section: Regulation Of the Hbp Pathway By The Androgen Receptormentioning

confidence: 99%

O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells

et al. 2013

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Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked b-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n ¼ 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n ¼ 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells. Cancer Res; 73(16); 5277-87. Ó2013 AACR.

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Section: Regulation Of the Hbp Pathway By The Androgen Receptormentioning

confidence: 99%

O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells

et al. 2013

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“…ARCaP E cells (5x10 4 ) were added to poly-L-lysine-coated chamber slides and cultured for 24 h. The cells were fixed in 4% paraformaldehyde, permeabilized with 0.25% Triton X-100 in PBS and blocked with 10% donkey serum, then stained with goat polyclonal primary antibody against EGFR (sc-31156, Santa Cruz Biotechnology, Dallas, TX, USA), and rabbit polyclonal primary antibody against GLI-1 (ab92611, Abcam, Cambridge, MA, USA). After rinsing, the primary antibodies were respectively detected with Alexa Fluor ® 488 donkey anti-goat (A-11055, Invitrogen, Grand Island, NY, USA) or Alexa Fluor ® 488 goat anti-rabbit secondary antibodies (Invitrogen), and the nuclei were labeled with DAPI (0.5 mg/ml) as previously described (24,25).…”

Section: Methodsmentioning

confidence: 99%

“…Androgen ablation therapy is an effective treatment for hormone-dependent prostate cancer; however, a subset of patients ultimately develops hormone refractory disease (3)(4)(5). Therefore, it is necessary to identify and characterize important regulators of aggressive prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Role of GLI-1 in epidermal growth factor-induced invasiveness of ARCaPE prostate cancer cells

et al. 2013

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Abstract. Epidermal growth factor (EGF) signaling and Hedgehog (HH) signaling are both involved in prostate cancer (PCa) progression, yet the mechanisms through which these two pathways are synergistically linked require elucidation. In the present study, we aimed to ascertain how EGF and the HH signaling transcription factor GLI-1 are linked in prostate cancer invasiveness. ARCaP human prostate cancer cells, which included ARCaP E and ARCaP M cells, were used as a model in the present study. The expression of EGF receptor (EGFR) and the HH signaling transcriptional factor GLI-1 were detected in ARCaP E cells by immunofluorescence, and the ARCaP E cells were treated with human recombinant EGF protein (hrEGF) for 4 consecutive days in vitro. Transwell invasion assays were performed in the ARCaP E cells following treatment with DMSO (vehicle control), hrEGF, GATN61 (GLI-1-specific inhibitor), hrEGF plus GANT61 and in the ARCaP M cells. The expression of phosphorylated extracellular signal regulated kinase (p-ERK), total ERK and GLI-1 was detected by western blotting in ARCaP E cells at different timepoints following treatment with hrEGF. The expression of EGFR and GLI-1 was detected in ARCaP E cells, which exhibited a cobblestone-like morphology, while after treatment with hrEGF, the cell morphology was altered to a spindle-shaped mesenchymal cell morphology. Transwell invasion assays demonstrated that hrEGF dramatically enhanced the invasive capability of the ARCaP E cells (P<0.05). Additionally, western blot assay demonstrated that the expression levels of p-ERK and GLI-1 in ARCaP E cells increased in a time-dependent manner after treatment with hrEGF (P<0.05); however, the expression levels of total ERK in the cells remained relatively unchanged. It also demonstrated that the GLI-1 inhibitor GANT61 could reverse the enhanced invasive effect induced by EGF in ARCaP E cells (P<0.05). Our preliminary in vitro study showed that EGF signaling may increase the invasive capability of ARCaP E human prostate cancer cells via upregulation of p-ERK and the HH signaling transcriptional factor GLI-1. Additionally, this enhanced cell invasive effect was reversed by a GLI-1-specific inhibitor in vitro. Consequently, it indicates that both EGF and HH signaling are synergistically involved in the progression of human prostate cancer ARCaP cells, and GLI-1 may be one of the important effectors, which is activated by EGF downstream signaling, to promote the invasiveness of ARCaP E prostate cancer cells.

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“…For patients with metastatic spread of prostate cancer, such as the patient in this case, the treatment of choice is androgen-deprivation therapy (ADT) (2,3). ADT has been reported to lead to remission in as many as 80% of patients with advanced prostate carcinoma (3,4). ADT is used in advanced prostate cancer to relieve pain, prevent pathologic fractures, and prevent neurologic complications (4).…”

Section: Discussion Hormone Therapymentioning

confidence: 99%

Hormone Therapy in Prostate Cancer

Currie

Haase

Hashmi

et al. 2013

Journal of Nuclear Medicine Technology

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The role of nuclear medicine diagnostic bone scanning is well established in prostate cancer. This case provides an insight into the specific role that bone scanning plays in monitoring response to hormone therapy and an example of significant global skeletal response. The case highlights the remarkable efficacy of timely hormone therapy in high-grade prostate cancer with widespread bony metastasis. In addition, the range of hormone therapy currently available for clinical application in the management of metastatic prostate cancer is detailed. Finally, the case represents an incidental diagnosis of prostate cancer after evaluation of nonspecific symptoms. We present a case study that provides an insight into the specific role that bone scanning plays in monitoring response to hormone therapy. The case highlights the remarkable efficacy of timely hormone therapy in high-grade prostate cancer with widespread bony metastasis. CASE REPORTAn 83-y-old man presented for evaluation of reported weight loss and constipation. These symptoms were initially assessed by CT of the chest, abdomen, and pelvis. The findings were unremarkable, although a left renal staghorn calculus was noted. Despite no previous history of neoplasia, extensive sclerotic lesions were noted throughout the axial skeleton. This finding, combined with the observation of an irregular prostate contour (without enlargement), raised suspicion of previously undiagnosed widespread metastatic prostate carcinoma. Subsequent follow-up revealed a prostate-specific antigen (PSA) level of 823 mg/L (normal, ,4 mg/L) and bone scan findings consistent with widespread skeletal metastases (Fig. 1). Subsequent prostate biopsy confirmed aggressive prostate carcinoma with a Gleason score of 9 (1). The patient commenced hormone therapy using bicalutamide (150 mg; Cosudex [AstraZeneca]) daily (oral tablet) and leuprorelin (30 mg; Lucrin [AbbVie]) depot (intramuscular injection) every 4 mo. The medications were well tolerated. At week 4, goserelin (Zoladex; AstraZeneca), a 10.8-mg subcutaneous implant (1 dose at 3 monthly intervals), was added to the patient's antitumor therapeutic armamentarium.At 5 mo after the commencement of therapy, the PSA level had normalized to 0.39 ug/L. It dropped further to 0.11 mg/L at 10 mo, corresponding to scintigraphic resolution of bony metastatic changes on the follow-up nuclear medicine bone scan (Fig. 2).

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Landmarks in hormonal therapy for prostate cancer

Cited by 24 publications

References 70 publications

O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells

O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells

Role of GLI-1 in epidermal growth factor-induced invasiveness of ARCaPE prostate cancer cells

Hormone Therapy in Prostate Cancer

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