Current topics and perspectives relating to hormone therapy for prostate cancer

Suzuki, Hiroyoshi; Igarashi, Takashi; Kawamura, Koji; Yano, Masashi; Takano, Makoto; Utsumi, Takanobu; Naya, Yukio; Ichikawa, Tomohiko

doi:10.1007/s10147-008-0830-y

Cited by 23 publications

(15 citation statements)

References 41 publications

(41 reference statements)

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“…Long-term androgen deprivation downregulates AR expression and induces EMT, which often lead to recurrent prostate tumor growth (Liu et al 2012). Clinical evidence also suggests that intermittent, rather than continuous, androgen deprivation therapy is more beneficial to patients with locally advanced, metastatic prostate tumors (Boccon-Gibod et al 2007, Suzuki et al 2008. Our study also hints that the loss of AR expression favors EMT in AI PCa cells.…”

Section: Discussionsupporting

confidence: 53%

Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer

Jacob¹,

Nayak²,

Fernandes³

et al. 2014

Endocrine-Related Cancer

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Zinc finger E-box-binding protein 2 (ZEB2) is known to help mediate the epithelialto-mesenchymal transition, and thereby it facilitates cancer metastasis. This study was initiated to explore whether ZEB2 expression differs in prostate cancer (PCa, nZ7) and benign prostatic hyperplasia (BPH, nZ7) tissues. In PCa tissues, the levels of both immunoreactive ZEB2 and androgen receptor (AR) were found to be significantly higher (P!0.05) when compared with BPH tissues. Co-regulation of AR and ZEB2 prompted us to investigate the role of androgenic stimuli in ZEB2 expression. ZEB2 expression was found to be significantly (P!0.05) upregulated after androgen stimulation and downregulated following AR silencing in LNCaP cells, an androgen-dependent PCa cell line. This finding suggested AR as a positive regulator of ZEB2 expression in androgen-dependent cells. Paradoxically, androgen-independent (AI) cell lines PC3 and DU145, known to possess low AR levels, showed significantly (P!0.05) higher expression of ZEB2 compared with LNCaP cells. Furthermore, forced expression of AR in PC3 (PC3-AR) and DU145 (DU-AR) cells led to reductions in ZEB2 expression, invasiveness, and migration. These cells also exhibited an increase in the levels of E-cadherin (a transcriptional target of ZEB2). Co-transfection of AR and ZEB2 cDNA constructs prevented the decline in invasiveness and migration to a significant extent. Additionally, ZEB2 downregulation was associated with an increase in miR200a/miR200b levels in PC3-AR cells and with a decrease in miR200a/miR200b levels in AR-silenced LNCaP cells. Thus, AR acts as a positive regulator of ZEB2 expression in androgendependent cells and as a negative regulator in AI PCa cells.

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Section: Discussionsupporting

confidence: 53%

Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer

Jacob¹,

Nayak²,

Fernandes³

et al. 2014

Endocrine-Related Cancer

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“…The mainstay of treatment for metastatic prostate cancer is androgen deprivation therapy (ADT), such as luteinizing hormone-releasing hormone (LHRH) agonists, anti-androgen and their combination, named maximal androgen blockade (MAB) (5)(6)(7). Although the majority of patients with metastatic disease initially respond to hormonal therapy, almost all of them will eventually progress after an average 18-24 months, despite maintenance of castrate serum testosterone levels <50 ng/ml (8).…”

Section: Introductionmentioning

confidence: 99%

Novel strategies in the treatment of castration-resistant prostate cancer (Review)

et al. 2012

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Abstract. Prostate cancer is the most common cancer in men in Europe and the United States, and the third leading cause of death from cancer in Europe. Survival of prostate cancer cells is dependent on the activation of androgen receptors (AR), that are overexpressed in this tumor. Furthermore, ~90% of prostate cancer patients that respond to first-line androgen deprivation therapy (ADT) undergo rapid progression. This condition is defined as castration-resistant prostate cancer (CRPC). Docetaxelbased regimens significantly improve overall survival (OS) in patients with CRPC and represent the only treatment strategy approved by the Food and Drug Administration (FDA). Recently, abiraterone (second hormonal therapy) and cabazitaxel (new taxane) have been shown to improve survival in patients with CRPC who progressed following docetaxel-based chemotherapy. Vaccine therapy has also been demonstrated to improve OS in patients with asymptomatic or minimally symptomatic metastatic CRPC. Additional therapeutic targets have been analyzed in prostate cancer, including apoptosis, angiogenic receptors, vitamin D and Src pathways. Several phase II studies are ongoing. The high frequency of prostate cancer-related metastatic bone disease has led to consider this pathway as a therapeutic target. To this end, several bone-targeted agents have been investigated, most notably zoledronic acid, which is highly effective at stabilizing the bone and preventing skeletal complications. More recently, a nuclear factor-β ligand (RANKL) inhibitor, denosumab, has been developed for the treatment of bone metastases.

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“…Orchiectomy is a simple surgical procedure, but it has fallen out of favor given its psychological impact and viable medical alternatives for androgen deprivation (4). GnRH agonist therapy is widely used as a medical and reversible castration.…”

mentioning

confidence: 99%

Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

Zhang

Cheng

et al. 2010

Endocrinology

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The androgen-androgen receptor signaling pathway plays an important role in the pathogenesis of prostate cancer. Accordingly, androgen deprivation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel pregnane X receptor (PXR)-mediated and metabolism-based mechanism to reduce androgenic tone. PXR is a nuclear receptor previously known as a xenobiotic receptor regulating the expression of drug metabolizing enzymes and transporters. We showed that genetic (using a PXR transgene) or pharmacological (using a PXR agonist) activation of PXR lowered androgenic activity and inhibited androgen-dependent prostate regeneration in castrated male mice that received daily injections of testosterone propionate by inducing the expression of cytochrome P450 (CYP)3As and hydroxysteroid sulfotransferase (SULT)2A1, which are enzymes important for the metabolic deactivation of androgens. In human prostate cancer cells, treatment with the PXR agonist rifampicin (RIF) inhibited androgen-dependent proliferation of LAPC-4 cells but had little effect on the growth of the androgen-independent isogenic LA99 cells. Down-regulation of PXR or SULT2A1 in LAPC-4 cells by short hairpin RNA or small interfering RNA abolished the RIF effect, indicating that the inhibitory effect of RIF on androgens was PXR and SULT2A1 dependent. In summary, we have uncovered a novel function of PXR in androgen homeostasis. PXR may represent a novel therapeutic target to lower androgen activity and may aid in the treatment and prevention of hormone-dependent prostate cancer. (Endocrinology 151: 5721-5729, 2010) P rostate cancer is the most common malignancy diagnosed in American men and the second leading cause of male cancer mortality (1). In the 1940s, Charles Huggins found that metastatic prostate cancer responded to androgen deprivation therapy (ADT) (2), which has since become the mainstay of treatment for locally advanced and metastatic prostate cancer.The ADT strategies in prostate cancer patients include orchiectomy and the use of GnRH (also known as LHRH) agonists or antagonists, steroidal and nonsteroidal antiandrogens, and inhibitors for the 5␣-reductase (3). Orchiectomy is a simple surgical procedure, but it has fallen out of favor given its psychological impact and viable medical alternatives for androgen deprivation (4). GnRH agonist therapy is widely used as a medical and reversible castration. GnRH agonists induce a transient increase in plasma testosterone (T) levels during the first week of treatment, causing a "flare" reaction in prostate cancer patients (5). GnRH antagonists do not cause a T surge, but they could be associated with an enhanced risk of ana-

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Current topics and perspectives relating to hormone therapy for prostate cancer

Cited by 23 publications

References 41 publications

Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer

Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer

Novel strategies in the treatment of castration-resistant prostate cancer (Review)

Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

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