Potential Mechanism for the Effects of Dexamethasone on Growth of Androgen-Independent Prostate Cancer

Nishimura, Kazuo; Nonomura, Norio; Satoh, Eiichi; Harada, Yasunori; Nakayama, Masashi; Tokizane, Takashi; Fukui, Toshikazu; Ono, Yutaka; Inoue, Hitoshi; Shin, Masaru; Tsujimoto, Yuichi; Takayama, Hitoshi; Aozasa, Katsuyuki; Okuyama, Äkïhïko

doi:10.1093/jnci/93.22.1739

Cited by 132 publications

(124 citation statements)

References 31 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…Reporter gene assay showed that the promoter fragment containing this GRE motif was activated by androgen treatment at AR-dependent manner in LNCaP cells that are null of glucocorticoid receptor (GR). 35 Because the AR and the GR are closely related members in the steroid hormone receptor family, 22 it is plausible that this GRE (termed as ARE-1) motif is involved in androgen-induced SGK-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

et al. 2007

View full text Add to dashboard Cite

Androgen receptor (AR) is a critical factor in the development and progression of prostate cancer. We and others recently demonstrated that eliminating AR expression leads to apoptotic cell death in AR-positive prostate cancer cells. To understand the mechanisms of AR-dependent survival, we performed a genome-wide search for AR-regulated survival genes. We found that serum/glucocorticoid-induced protein kinase-1 (SGK-1) mRNA levels were significantly upregulated after androgen stimulation, which was confirmed to be AR dependent. Promoter analysis revealed that the AR interacted with the proximal and distal regions of the sgk1 promoter, leading to sgk-1 promoter activation after androgen stimulation. Functional assays demonstrated that SGK-1 was indispensable for the protective effect of androgens on cell death induced by serum starvation. SGK-1 overexpression not only rescued cells from AR small-interfering RNA (siRNA)-induced apoptosis, but also enhanced AR transactivation, even in the absence of androgen. Additionally, SGK-1 siRNA reduced AR transactivation, indicating a positive feedback effect of SGK-1 expression on AR-mediated gene expression and cellular survival. Taken together, our data suggest that SGK-1 is an androgen-regulated gene that plays a pivotal role in AR-dependent survival and gene expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Along this line, high serum levels of IL-6 in PAC patients have been linked to disease progression, hormone-independence and chemotherapy resistance (Nakashima et al, 2000;Sanchez-Perez et al, 2002;Michalaki et al, 2004). Also, dexamethasone, a glucocorticoid used commonly for prostate cancer treatment, disrupts the NF-kB-IL-6 pathway and this is thought to mediate the antitumour effect (Nishimura et al, 2001). Finally, recent evidence in a phase I clinical trial has suggested that the proteasome inhibitor bortezomib has activity against human prostate cancer and reduces the expression of serum IL-6 and PSA levels in some patients (Papandreou and Logothetis, 2004).…”

Section: Discussionmentioning

confidence: 99%

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

et al. 2005

View full text Add to dashboard Cite

Nuclear factor (NF)-kB/p65 regulates the transcription of a wide variety of genes involved in cell survival, invasion and metastasis. We characterised by immunohistochemistry the expression of NF-kB/p65 protein in six histologically normal prostate, 13 high-grade prostatic intraepithelial neoplasia (PIN) and 86 prostate adenocarcinoma specimens. Nuclear localisation of p65 was used as a measure of NF-kB active state. Nuclear localisation of NF-kB was only seen in scattered basal cells in normal prostate glands. Prostatic intraepithelial neoplasias exhibited diffuse and strong cytoplasmic staining but no nuclear staining. In prostate adenocarcinomas, cytoplasmic NF-kB was detected in 57 (66.3%) specimens, and nuclear NF-kB (activated) in 47 (54.7%). Nuclear and cytoplasmic NF-kB staining was not correlated (P ¼ 0.19). By univariate analysis, nuclear localisation of NF-kB was associated with biochemical relapse (P ¼ 0.0009; log-rank test) while cytoplasmic expression did not. On multivariate analysis, serum preoperative prostate specific antigen (P ¼ 0.02), Gleason score (P ¼ 0.03) and nuclear NF-kB (P ¼ 0.002) were independent predictors of biochemical relapse. These results provide novel evidence for NF-kB/p65 nuclear translocation in the transition from PIN to prostate cancer. Our findings also indicate that nuclear localisation of NF-kB is an independent prognostic factor of biochemical relapse in prostate cancer.

show abstract

“…In addition, we evaluated the effect of dexamethasone (DEX) on the luciferase activities of LF4 and LF7 in the cells co-transfected with a GR expression vector. This is because DEX is known to downregulate GR expression in LANCaP cells (19,20). First, we examined the luciferase activities of LF4 in the LNCaP cells, which was co-transfected with either hGR· or hGRß, with or without dexamethasone (DEX) treatment.…”

Section: Downregulation Of 15-lox-2 Promoter Activity By the Glucocormentioning

confidence: 99%

Downregulation of 15-lipoxygenase 2 by glucocorticoid receptor in prostate cancer cells

Feng

Bai²,

Yang³

et al. 2010

Int J Oncol

View full text Add to dashboard Cite

Abstract. 15-lipoxygenase 2 (15-LOX-2) is lost or significantly reduced in prostate cancer. However, the regulation of 15-LOX-2 remains unclear. In this study, we independently cloned the 5' upstream promoter fragments of 15-LOX-2 gene. Target DNA fragments each were cloned into an expression vector containing luciferase reporter gene, which were called LF1(-1533/+87), LF2(-628/+87), LF3(-253/+87), LF4(-157/ +87), LF5(-33/+87), LF6(-253/+1), and LF7(-157/+1). Each of these individual promoter fragments was transfected into primary prostate epithelial cells and prostate cancer LNCaP cells. The promoter activity gradually decreased with progressive deletions from LF2 to LF4. A significant drop was noted in the LF5. LF6 and LF7 that did not contain the 87-bp region downstream the transcription start site (TSS) have significant luciferase activities similar to those of corresponding fragments (LF3 and LF4) that contain 87-bp region downstream the TSS. This suggests that the 125-bp region (-157 to -33) of LF4 is critical for the promoter activity of 15-LOX-2 in the primary prostate epithelial cells PrEC and cancer cells LNCaP. Moreover, we discovered a specific glucocorticoid receptor (GR) responsive element (GRE) in this key region. The luciferase activities of the LF4 and LF7 were decreased in the LNCaP cells co-transfected with GR (hGR· or hGRß) expression vectors. This inhibitory effect is reversed after treatments with dexamethasone or two specific GR inhibitors (siRNAs of GR and RU486). Results from this study suggest a 125-bp region (-157 to -33) is critical for the 15-LOX-2 promoter activity in prostate epithelial cells and cancer cells, which was significantly downregulated by GR via the GRE in this region.

show abstract

Potential Mechanism for the Effects of Dexamethasone on Growth of Androgen-Independent Prostate Cancer

Abstract: Dexamethasone inhibited the growth of GR-positive cancers, possibly through the disruption of the NF-kappaB-IL-6 pathway.

Cited by 132 publications

References 31 publications

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

Downregulation of 15-lipoxygenase 2 by glucocorticoid receptor in prostate cancer cells

Contact Info

Product

Resources

About