Prostate cancer: molecular biology of early progression to androgen independence.

1999 ◽  
pp. 487-502 ◽  
Author(s):  
M D Sadar ◽  
M Hussain ◽  
N Bruchovsky
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Molecular Biology ◽  
Tumour Progression ◽  
Specific Antigen ◽  
Signal Transduction Pathway ◽  
Underlying Mechanism ◽  
Amino Terminus ◽  
Androgen Independence ◽  
Androgen Withdrawal

To improve the therapy for prostate cancer, it will be necessary to address the problems of progression to androgen independence and the process of metastatic spread of tumour. The complexity of the latter condition is likely to mitigate against the immediate development of relevant therapeutic approaches. However, the basis of androgen independence appears to be a problem of simpler dimensions and more amenable to treatment with current therapeutic technology. Since early tumour progression can be detected by an incomplete prostate-specific antigen (PSA) response to androgen withdrawal therapy, a study of the molecular biology of PSA gene regulation may well provide insight into new methods for preventing or delaying this problem. Mounting evidence suggests that ligand-independent activation of the androgen receptor may be one underlying mechanism of androgen independence. In the absence of androgen, a compensatory increase in the activity of cAMP-dependent protein kinase (PKA) enhances the ability of the androgen receptor to bind to the response elements regulating PSA gene expression. The activation of the androgen receptor through up-regulation of the PKA signal transduction pathway involves the amino-terminus of the androgen receptor, the function of which may be altered either by modifications such as phosphorylation, or through interactions with co-regulators or other proteins. Of therapeutic interest is the fact that this effect can be counteracted experimentally by the anti-androgen, bicalutamide, and clinically by several other similar agents. We speculate that the inhibition of PKA-activated androgen receptor might also be accomplished by decoy molecules that can bind to the relevant activated site on the amino-terminus or competitively interact with proteins recruited by the PKA pathway that are responsible for activating the receptor in the absence of androgen. Such molecules might include small mimetic substances or agents that can gain access to the nucleus of the cell.

scholarly journals Zinc Inhibits Expression of Androgen Receptor to Suppress Growth of Prostate Cancer Cells

2018 ◽  
Vol 19 (10) ◽  
pp. 3062 ◽  
Author(s):  
Phuong To ◽  
Manh-Hung Do ◽  
Young-Suk Cho ◽  
Se-Young Kwon ◽  
Min Kim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Transcriptional Control ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Underlying Mechanism ◽  
Significant Loss ◽  
Intracellular Zinc

The prostate gland contains a high level of intracellular zinc, which is dramatically diminished during prostate cancer (PCa) development. Owing to the unclear role of zinc in this process, therapeutic applications using zinc are limited. This study aimed to clarify the role of zinc and its underlying mechanism in the growth of PCa. ZnCl2 suppressed the proliferation of androgen receptor (AR)-retaining PCa cells, whereas it did not affect AR-deficient PCa cells. In LNCaP and TRAMP-C2 cells, zinc downregulated the expression of AR in a dose- and time-dependent fashion. Zinc-mediated AR suppression accordingly inhibited the androgen-mediated transactivation and expression of the androgen target, prostate specific antigen (PSA). This phenomenon resulted from facilitated protein degradation, not transcriptional control. In studies using mice bearing TRAMP-C2 subcutaneous tumors, the intraperitoneal injection of zinc significantly reduced tumor size. Analyses of both xenograft tumors and normal prostates showed reduced expression of AR and increased cell death. Considering the significant loss of intracellular zinc and the dominant growth-modulating role of AR during PCa development, loss of zinc may be a critical step in the transformation of normal cells to cancer cells. This study provides the underlying mechanism by which zinc functions as a PCa suppressor, and forms the foundation for developing zinc-mediated therapeutics for PCa.

scholarly journals The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity

2003 ◽  
Vol 31 (1) ◽  
pp. 169-183 ◽  
Author(s):  
B Nan ◽  
T Snabboon ◽  
E Unni ◽  
Yuan X-J ◽  
YE Whang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Suppressor ◽  
Transcriptional Activity ◽  
Specific Antigen ◽  
Suppressor Gene ◽  
Dominant Negative ◽  
Site Directed Mutagenesis ◽  
Wild Type ◽  
Androgen Independence

To investigate whether the tumor suppressor gene PTEN affects the activity of the androgen receptor (AR), we monitored the expression of the apoptotic gene HA-Bax (inserted in an adenovirus where it is driven by the AR-responsive promoter ARR(2)PB) in the presence or absence of dihydrotestosterone, in PTEN (+) or (-) prostate cancer cell lines, infected with an adenovirus containing wild-type PTEN (Av-CMV-PTEN) or a control LacZ-expressing construct. Our results showed that AR transcriptional activity was antagonized by PTEN expression. This antagonism was not cell line dependent, as it was observed in both LNCaP and LAPC-4 cells, or promoter dependent, as it was observed for a reporter gene (HA-Bax) driven by an exogenous androgen-responsive promoter (the ARR(2)PB promoter), and for a native gene (prostate-specific antigen; PSA) driven by an endogenous AR-responsive promoter. Additional experiments performed with viruses containing constitutively active (Adeno-myrAkt) or dominant negative (Adeno-dnAkt) forms of Akt demonstrated that Akt, a protein kinase whose activation is known to be inhibited by PTEN, mediated the observed antagonism between PTEN and AR transcriptional activity. Recently, two putative Akt phosphorylation sites have been identified in the AR sequence. Site-directed mutagenesis was utilized to convert these two serine into alanine residues. The resulting construct, named CMV-AR S213A&S791A was transfected in AR (-) and PTEN (-) PC-3 cells in the presence or absence of Av-CMV-PTEN and of two reporter plasmids (GRE(2)E1b-Luc and PSA P/E-luc) containing the luciferase gene driven by well-characterized androgen responsive promoters. These experiments demonstrated that, similarly to the wild-type molecule, AR S213A&S791A was transcriptionally inhibited by PTEN, suggesting that Akt does not have an effect on AR transcription by direct phosphorylation, but probably by affecting the availability of a downstream molecule whose main mechanism of action is that of modulating AR transcription. The data presented here suggest that loss of PTEN function may facilitate activation of AR signaling and progression to androgen independence in prostate cancer.

scholarly journals SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana Trnski ◽  
Maja Sabol ◽  
Sanja Tomić ◽  
Ivan Štefanac ◽  
Milanka Mrčela ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Therapy Resistance ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Androgen Independence ◽  
Androgen Receptor Activity ◽  
Signaling Activation ◽  
Androgen Independent

AbstractProstate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

scholarly journals Role of Testosterone Levels on the Combinatorial Effect of Boswellia serrata Extract and Enzalutamide on Androgen Dependent LNCaP Cells and in Patient Derived Cells

2021 ◽  
Vol 20 ◽  
pp. 153473542199682
Author(s):  
Prathesha Pillai ◽  
Ginil Kumar Pooleri ◽  
Shantikumar V. Nair
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Early Stage ◽  
Therapeutic Option ◽  
Specific Antigen ◽  
Cell Killing ◽  
Receptor Expression ◽  
Lncap Cells ◽  
Boswellia Serrata ◽  
Physiological Serum

Co-therapy with herbal extracts along with current clinical drugs is being increasingly recognized as a useful complementary treatment for cancer. The anti-cancer property of the phyto-derivative acetyl-11 keto β boswellic acid (AKBA) has been studied in many cancers, including prostate cancer. However, the whole extract of the gum resin Boswellia serrata (BS) and anti-androgen enzalutamide has not been explored in prostate cancer to date. We hypothesized that the BS extract containing 30% (AKBA) with enzalutamide acted synergistically in the early phase of cancer, especially in LNCaP cells, by inhibiting androgen receptor (AR) and by reducing cell proliferation, and further, that the extract would be superior to the action of the active ingredient AKBA when used alone or in combination with enzalutamide. To test our hypothesis, we treated LNCaP cells with BS extract or AKBA and enzalutamide both individually and in combination to analyze cell viability under different levels of dihydrotestosterone (DHT). The inhibition of androgen receptor (AR) followed by the expression of prostate-specific antigen (PSA) and the efflux mechanism of the cells were analyzed to determine the effect of the combination on the cellular mechanism. Cells derived from prostate cancer patients were also tested with the combination. Only 6 µM enzalutamide along with BS in the range of 4.1 µg/ml to 16.4 µg/ml gave the best synergistic results with nearly 50% cell killing even though standard enzalutamide doses were as high as 48 µM. Cell killing was most effective at intermediate DHT concentrations of approximately 1 nM, which corresponds to normal physiological serum levels of DHT. The Pgp expression level and the androgen receptor expression levels were reduced under the combination treatment; the former helping to minimize drug efflux and the latter by reducing the sensitivity to hormonal changes. Furthermore, the combination reduced the PSA level secreted by the cells. In contrast, AKBA could not achieve the needed synergism for adequate cell killing at equivalent concentrations. The combination of enzalutamide and BS extract containing 30% AKBA because of their synergistic interaction is an attractive therapeutic option for treating early stage (hormone-dependent) prostate cancer and is superior to the use of AKBA alone.

scholarly journals Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors

2021 ◽  
Author(s):  
Fred Saad ◽  
Martin Bögemann ◽  
Kazuhiro Suzuki ◽  
Neal Shore
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Second Generation ◽  
Imaging Techniques ◽  
Specific Antigen ◽  
Conventional Imaging ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Therapeutic Decisions ◽  
Consensus Statements

Abstract Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit–risk profile of potential treatments is required. Methods In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function. Results and conclusions While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit–risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

scholarly journals The role of the androgen receptor as a driver and mitigator of cellular stress

2020 ◽  
Vol 65 (2) ◽  
pp. R19-R33
Author(s):  
Dimitrios Doultsinos ◽  
Ian Mills
Keyword(s):  
Prostate Cancer ◽  
Protein Synthesis ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Nuclear Hormone Receptor ◽  
Biological Processes ◽  
Normal Prostate ◽  
Mtor Activity

Prostate cancer is a high-incidence male cancer, which is dependent on the activity of a nuclear hormone receptor, the androgen receptor (AR). Since the AR is required for both normal prostate gland development and for prostate cancer progression, it is possible that prostate cancer evolves from perturbations in AR-dependent biological processes that sustain specialist glandular functions. The archetypal example of course is the use of prostate specific antigen (PSA), an organ-type specific component of the normal prostate secretome, as a biomarker of prostate cancer. Furthermore, localised prostate cancer is characterised by a low proliferative index and a heterogenous array of somatic mutations aligned to a multifocal disease pattern. We and others have identified a number of biological processes that are AR dependent and represent aberrations in significant glandular processes. Glands are characterised by high rates of metabolic activity including protein synthesis supported by co-dependent processes such as glycosylation, organelle biogenesis and vesicle trafficking. Impairments in anabolic metabolism and in protein folding/processing will inevitably impose proteotoxic and oxidative stress on glandular cells and, in particular, luminal epithelial cells for which secretion is their primary function. As cancer develops there is also significant metabolic dysregulation including impaired negative feedback effects on glycolytic and anabolic activity under conditions of hypoxia and heightened protein synthesis due to dysregulated PI 3-kinase/mTOR activity. In this review we will focus on the components of the AR regulome that support cancer development as well as glandular functions focussing on the unfolded protein response and on regulators of mTOR activity.

Polymorphisms in the androgen receptor and the prostate-specific antigen genes and prostate cancer risk

The Prostate ◽  
2005 ◽  
Vol 65 (1) ◽  
pp. 58-65 ◽  
Author(s):  
Claudia A. Salinas ◽  
Melissa A. Austin ◽  
Elaine O. Ostrander ◽  
Janet L. Stanford
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Risk ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Prostate Cancer Risk

Molecular Biology Underlying the Clinical Heterogeneity of Prostate Cancer: An Update

2009 ◽  
Vol 133 (7) ◽  
pp. 1033-1040 ◽  
Author(s):  
A. Craig Mackinnon ◽  
Benjamin C. Yan ◽  
Loren J. Joseph ◽  
Hikmat A. Al-Ahmadie
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Molecular Biology ◽  
Gene Rearrangement ◽  
Molecular Characteristics ◽  
Early Event ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Development Of Resistance ◽  
Prostate Cancers

Abstract Context.—Recent studies have uncovered a number of possible mechanisms by which prostate cancers can become resistant to systemic androgen deprivation, most involving androgen-independent reactivation of the androgen receptor. Genome-wide expression analysis with microarrays has identified a wide array of genes that are differentially expressed in metastatic prostate cancers compared to primary nonrecurrent tumors. Recently, recurrent gene fusions between TMPRSS2 and ETS family genes have been identified and extensively studied for their role in prostatic carcinoma. Objective.—To review the recent developments in the molecular biology of prostate cancer, including those pertaining to the androgen receptor and the newly identified TMPRSS2-related translocations. Data Sources.—Literature review and personal experience. Conclusions.—Prostatic adenocarcinoma is a heterogeneous group of neoplasms with a broad spectrum of pathologic and molecular characteristics and clinical behaviors. Numerous mechanisms contribute to the development of resistance to androgen ablation therapy, resulting in ligand-independent reactivation of the androgen receptor, including amplification, mutation, phosphorylation, and activation of coreceptors. Multiple translocations of members of the ETS oncogene family are present in approximately half of clinically localized prostate cancers. TMPRSS2:ERG gene rearrangement appears to be an early event in prostate cancer and is not observed in benign or hyperplastic prostatic epithelium. Duplication of TMPRSS2:ERG appears to predict a worse prognosis. The relationship between TMPRSS2:ERG gene rearrangement and other morphologic and prognostic parameters of prostate cancer is still unclear.

Hormonal therapy of prostate cancer

2011 ◽  
pp. 1622-1634
Author(s):  
Ciara O’Hanlon Brown ◽  
Jonathan Waxman
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Specific Antigen ◽  
Intraepithelial Neoplasia ◽  
Peripheral Zone ◽  
Molecular Feature ◽  
Molecular Defects ◽  
Psa Testing ◽  
Seer Data ◽  
Prostate Cancers

Prostate cancer is the most common cancer to effect men and the second most common cause of cancer-related death. Premalignant change or prostatic intraepithelial neoplasia has been detected within the prostate glands of men under 30 years of age. The incidence of prostate cancer remains negligible until men reach their 40s from whence it rises steadily and by 80 years 70% of men have detectable tumours at autopsy (1). A majority of prostate cancers arise from the peripheral zone of the prostate and rarely cause obstructive symptoms. Consequently, prostate cancers have historically presented late, with symptoms of metastatic disease. The advent of prostate-specific antigen (PSA) testing has produced a stage shift so that at present over 90% of prostate cancers are diagnosed as organ-confined disease. PSA diagnosis has unmasked a subset of prostate tumours that exhibit an indolent growth pattern and appear destined to remain organ-confined tumours the patient dies with, and not from. US SEER data estimates a 50-year-old man has a 42% chance of developing prostate cancer but only a 3.6% chance of dying from the disease. Features, either clinical or molecular, which would allow clinicians to clearly differentiate indolent from aggressive disease while still at the organ-confined stage, have yet to be identified (1). Adenocarcinoma is the predominant histological subtype of prostate cancer, accounting for 95% of tumours. Prostatic adenocarcinomas arise from androgen receptor-positive epithelial cells. On histological examination, prostate cancers appear multifocal and demonstrate heterogeneity both within individual tumours and across populations. This has created an obstacle as researchers attempt to subclassify prostate cancer and identify the molecular defects responsible for driving prostatic carcinogenesis (1). Of prostate cancers, 80–90% are androgen receptor-positive at diagnosis (2), thus to date the androgen–androgen receptor axis is the sole molecular feature of this disease that has been successfully harnessed as a therapeutic target.

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