Few effective therapies exist for the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC may be caused by augmented androgen/androgen receptor (AR) ...signaling, generally involving AR overexpression. Aberrant androgen/AR signaling associated with AR overexpression also plays a key role in prostate carcinogenesis. Although AR overexpression could be attributed to gene amplification, only 10–20% of CRPCs exhibit AR gene amplification, and aberrant AR expression in the remaining instances of CRPC is thought to be attributed to transcriptional, translational, and post-translational mechanisms. Overexpression of AR at the protein level, as well as the mRNA level, has been found in CRPC, suggesting a key role for transcriptional regulation of AR expression. Since the analysis of the AR promoter region in the 1990s, several transcription factors have been reported to regulate AR transcription. In this review, we discuss the molecules involved in the control of AR gene expression, with emphasis on its transcriptional control by transcription factors in prostate cancer. We also consider the therapeutic potential of targeting AR expression.
Oxidative stress caused by an increase in reactive oxygen species levels or a decrease in cellular antioxidant capacity can evoke the modulation of various cellular events including androgen receptor ...(AR) signaling via direct or indirect interactions. In this review, we summarize the mechanisms of AR activation by oxidative stress including: i) AR overexpression; ii) AR activation by AR co-regulators or intracellular signal transduction pathways; iii) generation of AR mutations or splice variants; and iv) de novo androgen synthesis. AR signaling augmented by oxidative stress appears to contribute to pro-survival and anti-apoptotic effects in prostate cancer cells in response to androgen deprivation therapy. In addition, AR signaling suppresses anti-survival and pro-apoptotic effects in prostate cancer cells in response to various cytotoxic and tumor-suppressive interventions including taxanes and radiation through the modulation of βIII-tubulin and ataxia telangiectasia-mutated kinase expression respectively. Taken together, AR signaling appears to render prostate cancer cells refractory to various therapeutic interventions including castration, taxanes, and radiation, indicating that AR signaling is a comprehensive resistant factor and crucial target for prostate cancer treatment.
Objective: To assess the morbidity secondary to ultrasound‐guided systematic prostate biopsy in Japan.
Methods: Five hundred and forty‐eight principal urological training institutions certified by ...the Japanese Urological Association participated in the survey. A retrospective analysis of complications after prostate biopsy was conducted.
Results: Medical records of 212 065 procedures carried out between 2004 and 2006 were reviewed. Seventy‐six percent of procedures had been carried out transrectally, and 23% transperineally. Hematuria, rectal bleeding and hematospermia occurred in 12%, 5.9% and 1.2% of cases, respectively. Voiding symptoms were reported after biopsy in 1.9% of cases and urinary retention in 1.1%. Fever (>38°C) was observed in 1.1% and sepsis occurred in 0.07%. Hospitalization was required in 0.69% of cases for the treatment of biopsy‐related complications.
Conclusions: Overall, contemporary ultrasound‐guided systematic prostate biopsy is safely carried out in Japan. However, minor complications are not infrequent, whereas major ones remain very rare but life‐threatening if they occur. Thus, adequate information should be provided to patients undergoing prostate biopsy.
Objectives
To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer.
Methods
Data of patients with prostate ...cancer who had received hormone therapy were extracted from a nationwide community‐based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13 346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression‐free survival, cancer‐specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer.
Results
A positive family history was identified in 220 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate‐specific antigen level at diagnosis <100 ng/mL and those with low or intermediate Japan Cancer of the Prostate Risk Assessment.
Conclusions
Our findings show that familial prostate cancer has an early‐onset feature or is diagnosed earlier than sporadic prostate cancer. However, the prognosis of individuals with familial prostate cancer undergoing hormone therapy is comparable to those with sporadic prostate cancer.
Although androgen deprivation therapy for advanced prostate cancer initially exerts excellent anticancer effects, most prostate cancer treated with androgen deprivation therapy eventually recurs as ...castration-resistant prostate cancer (CRPC). Although aberrant kinase activation has been proposed as a mechanism of castration resistance, comprehensive kinase profiles in CRPC remain unknown. Therefore, we aimed to elucidate the kinome in CRPC as well as the role of key molecules.
We utilized a kinome array in androgen-dependent LNCaP and castration-resistant CxR cells. The effect of Y-box binding protein-1 (YB-1) on androgen receptor (AR) expression was examined by quantitative polymerase chain reaction and western blot analysis. The association between polymorphisms in the YB-1 gene determined by genotyping and YB-1 expression evaluated by immunohistochemistry in prostate cancer tissues, as well as outcome in metastatic prostate cancer, were investigated by the Cochran-Armitage test and the Cox proportional hazards model, respectively. All statistical tests were two-sided.
One hundred fifty-six of 180 kinase phosphorylation sites, including ERK and RSK, were activated in CRPC cells, leading to increased phosphorylation of YB-1, which is a key molecule in the progression to CRPC. YB-1 signaling regulated AR V7 expression, and YB-1 inhibition augmented the anticancer effect of enzalutamide. Moreover, polymorphism (rs12030724) in the YB-1 gene affected YB-1 expression in 93 prostate cancer tissues (YB-1 positive rate; 14.3% in TT, 40.0% in AT, and 52.9% in AA, P = .04) and associated with probability of progression in 104 metastatic prostate cancer case patients (AT/TT vs AA, hazard ratio = 0.49, 95% confidence interval = 0.32 to 0.77, P = .001).
YB-1 appears to be a promising target to inhibit the development of castration resistance, even at the AR variant-expressing stage. Polymorphism in the YB-1 gene may be a promising predictive biomarker in hormonal therapy.
Abstract Background Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are ...exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients. Objectives We aimed to investigate the prognosis of Japanese patients and their prognostic factors. Design, setting, and participants The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002. Measurements The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features. Results and limitations The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival. Conclusions The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.
Many advanced cancers receive cisplatin‐based chemotherapy. However, cisplatin resistance is a major obstacle for cancer chemotherapy. Foxo3a is a member of the Foxo transcription factor family, ...which modulates the expression of genes involved in DNA damage repair, apoptosis, and other cellular processes. In this study, we found that cisplatin‐resistant cells were more sensitive to the anticancer agent mithramycin than their parental cells, and had a decreased level of Foxo3a expression. Foxo3a knockdown increased cell proliferation and resistance to cisplatin. On the other hand, mithramycin stimulated Foxo3a expression through reactive oxygen species production and sensitized cells to cisplatin, which was abolished by Foxo3a knockdown, while the acetylation status of Foxo3a was decreased in response to cisplatin treatment and was lower in cisplatin‐resistant cells. Knockdown of Foxo3a‐associated acetyltransferase p300 promoted cancer‐cell growth and cisplatin resistance. In addition, non‐acetylation‐mimicking Foxo3a overexpression decreased cancer cell growth and sensitized cells to cisplatin less than wild‐type Foxo3a overexpression. The current work may contribute to the evaluation of the therapeutic potential of inducing the Foxo3a pathway and acetylating the Foxo3a transcription factor, and lead to the reevaluation of cancer treatments based on mithramycin.
(Cancer Sci 2010; 101: 1177–1185)
Y-box-binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and castration resistance in prostate cancer. ...However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer.
Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses.
EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor HR, 7.947; 95% confidence interval (CI), 3.527-20.508; P<0.0001.
We revealed the functional relationship between YB-1 and MAPK signaling and its biochemical relevance to the progression of prostate cancer. In addition, ERK2 expression was an independent prognostic factor. These findings suggest that both the ERK pathway and YB-1 may be promising molecular targets for prostate cancer diagnosis and therapeutics.
A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial ...was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (
n
= 25) or placebo with docetaxel and dexamethasone (
n
= 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%;
P
= 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (
P
= 0.018) and CTL (
P
= 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of < 11.2 ng/ml, but further clinical trials comparing OS are required.
Abstract Purpose To investigate the neurohumoral modulation of the contractility of muscularis mucosae (mucosa) of the bladder in comparison with those of detrusor smooth muscle. Materials and ...Methods Changes in the contractility of mucosa and detrusor bundles taken from guinea-pig bladders were measured using isometric tension recording. The morphological relationship between muscularis mucosae, blood vessels and their sensory innervation was examined using fluorescent immunohistochemistry. Results Meshworks of muscularis mucosae with numerous branches and anastomosis preferentially ran parallel with suburothelial blood vessels. Although PTHrP receptors were expressed in both detrusor and mucosa, PTHrP (1 nM), an endogenous detrusor relaxant, suppressed spontaneous contractions in detrusor but not mucosa. A higher concentration of PTHrP (10 nM) was required to inhibit mucosal contractility. Capsaicin (1 μM) abolished spontaneous contractions in mucosa, but had an excitatory action on detrusor contractility. Calcitonin gene-related peptide (hCGRP, 1 nM) attenuated spontaneous contractions of mucosa. Pretreatment with hCGRP 8-37 (2 μM), a CGRP antagonist, inhibited CGRP- or capsaicin-induced suppressions of spontaneous contractions. Consistently, CGRP-immunoreactive primary afferent nerves were abundant in muscularis mucosae. Conclusions Co-localisation of muscularis mucosae with the suburothelial microvasculature suggests that spontaneous contractions of mucosa might function to prevent stretching of the microvasculature upon bladder wall distension during storage phase. It is likely that PTHrP selectively suppresses spontaneous contractions in detrusor but not mucosa, and thus endogenous PTHrP may well increase bladder compliance without an associated distension-induced deformation of mucosal elements. Excessive stimulations of sensory nerves may suppress mucosal contractility by releasing CGRP.
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