Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells

Contrary to cell cycle–associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-depdent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks.

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Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2010.055 ◽

2011 ◽

Vol 5 (1) ◽

Author(s):

Harri Makkonen ◽

Jorma J. Palvimo

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Binding Sites ◽

Target Genes ◽

Three Dimensional ◽

Regulatory Elements ◽

Gene Promoters ◽

Loop Formation ◽

Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

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1α,25-Dihydroxyvitamin D3 Inhibits Growth of VCaP Prostate Cancer Cells Despite Inducing the Growth-Promoting TMPRSS2:ERG Gene Fusion

Endocrinology ◽

10.1210/en.2009-0991 ◽

2010 ◽

Vol 151 (4) ◽

pp. 1409-1417 ◽

Cited By ~ 28

Author(s):

Michele N. Washington ◽

Nancy L. Weigel

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Target Gene ◽

Target Genes ◽

Fusion Gene ◽

Critical Factor ◽

Synthetic Analog ◽

Prostate Cancer Cells ◽

Dihydroxyvitamin D3

Vitamin D receptor (VDR) agonists have been shown to reduce the growth of several prostate cancer cell lines. However, the effects of VDR activation have not been examined in the presence of the recently identified androgen-regulated TMPRSS2:ERG gene fusions, which occur in a high percentage of prostate cancers and play a role in growth and invasiveness. In a previous microarray study, we found that VDR activation induces TMPRSS2 expression in LNCaP prostate cancer cells. Here we show that the natural VDR agonist 1α,25-dihydroxyvitamin D3 and its synthetic analog EB1089 increase expression of TMPRSS2:ERG mRNA in VCaP prostate cancer cells; this results in increased ETS-related gene (ERG) protein expression and ERG activity as demonstrated by an increase in the ERG target gene CACNA1D. In VCaP cells, we were not able to prevent EB1089-mediated TMPRSS2:ERG induction with an androgen receptor antagonist, Casodex, although in LNCaP cells, as reported for some other common androgen receptor and VDR target genes, Casodex reduces EB1089-mediated induction of TMPRSS2. However, despite inducing the fusion gene, VDR agonists reduce VCaP cell growth and expression of the ERG target gene c-Myc, a critical factor in VDR-mediated growth inhibition. Thus, the beneficial effects of VDR agonist treatment override some of the negative effects of ERG induction, although others remain to be tested.

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Growth inhibition of androgen-responsive prostate cancer cells with brefeldin A targeting cell cycle and androgen receptor

Journal of Biomedical Science ◽

10.1186/1423-0127-17-5 ◽

2010 ◽

Vol 17 (1) ◽

pp. 5 ◽

Cited By ~ 8

Author(s):

Srinivas Rajamahanty ◽

Catherine Alonzo ◽

Shahrad Aynehchi ◽

Muhammad Choudhury ◽

Sensuke Konno

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Androgen Receptor ◽

Growth Inhibition ◽

Cancer Cells ◽

Brefeldin A ◽

Prostate Cancer Cells

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Cold Atmospheric Plasma Selectively Induces G0/G1 Cell Cycle Arrest and Apoptosis in AR-Independent Prostate Cancer Cells

10.21203/rs.3.rs-49986/v1 ◽

2020 ◽

Author(s):

Meng Ning ◽

Zhifa Zhang ◽

Lihui Yu ◽

Peiyu Han ◽

xiaofeng Dai

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Androgen Receptor ◽

Cancer Cells ◽

Atmospheric Plasma ◽

Prostate Cancer Cells ◽

Cold Atmospheric Plasma ◽

Prostate Cancers ◽

And Migration ◽

Physical Plasma

Abstract BackgroundAndrogen receptor-independent prostate cancers do not respond to androgen blockage therapies and suffer from high recurrence rate. We aim to contribute to the establishment of novel therapeutic approaches against such malignancies.Methods We examined whether and how cold atmospheric plasma delivers selectivity against AR-independent prostate cancers using human normal epithelial prostatic cells PNT1A and AR-negative DU145 prostate cancer cells.ResultsWe show that cold atmospheric plasma could selectively halt cell proliferation and migration in androgen receptor-independent cells as a result of induced cell apoptosis and G0/G1 stage cell cycle arrest, and such outcomes were achieved through modulations on the MAPK and NF-kB pathways in response to physical plasma induced intracellular redox level. ConclusionOur study reports cold atmospheric plasma induced reduction on the proliferation and migration of androgen receptor-independent prostate cancer cells that offers novel therapeutic insights on the treatment of such cancers, and provides the first evidence on physical plasma induced cell cycle G0/G1 stage arrest that warrants the exploration on the synergistic use of cold atmospheric plasma and drugs such as chemotherapies in eradicating such cancer cells.

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DNA licensing as a novel androgen receptor mediated therapeutic target for prostate cancer

Endocrine Related Cancer ◽

10.1677/erc-08-0205 ◽

2009 ◽

Vol 16 (2) ◽

pp. 325-332 ◽

Cited By ~ 28

Author(s):

Jason M D'Antonio ◽

Donald J Vander Griend ◽

John T Isaacs

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Androgen Receptor ◽

Dna Replication ◽

Cancer Cells ◽

Cancer Biology ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Malignant Prostate

During middle G1 of the cell cycle origins of replication orchestrate the ordered assembly of the pre-replication complex (pre-RC), allowing licensing of DNA required for DNA replication. Cyclin-dependent kinase activation of the pre-RC facilitates the recruitment of additional signaling factors, which triggers DNA unwinding and replication, while limiting such DNA replication to once and only once per cell cycle. For both the normal and malignant prostate, androgen is the major stimulator of cell proliferation and thus DNA replication. In both cases, the binding of androgen to the androgen receptor (AR) is required. However, the biochemical cascade involved in such AR-stimulated cell proliferation and DNA synthesis is dramatically different in normal versus malignant prostate cells. In normal prostate, AR-stimulated stromal cell paracrine secretion of andromedins stimulates DNA replication within prostatic epithelial cells, in which AR functions as a tumor suppressor gene by inducing proliferative quiescence and terminal differentiation. By direct contrast, nuclear AR in prostate cancer cells autonomously stimulates continuous growth via incorporation of AR into the pre-RC. Such a gain of function by AR-expressing prostate cancer cells requires that AR be efficiently degraded during mitosis since lack of such degradation leads to re-licensing problems, resulting in S-phase arrest during the subsequent cell cycle. Thus, acquisition of AR as part of the licensing complex for DNA replication represents a paradigm shift in how we view the role of AR in prostate cancer biology, and introduces a novel vulnerability in AR-expressing prostate cancer cells apt for therapeutic intervention.

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Androgen receptor remains critical for cell-cycle progression in androgen-independent CWR22 prostate cancer cells

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2007.01.004 ◽

2007 ◽

Vol 25 (2) ◽

pp. 178-179

Author(s):

Ron Rodriguez

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Androgen Receptor ◽

Cancer Cells ◽

Cell Cycle Progression ◽

Prostate Cancer Cells ◽

Cycle Progression ◽

Androgen Independent

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GADD45γ: a New Vitamin D-Regulated Gene that Is Antiproliferative in Prostate Cancer Cells

Endocrinology ◽

10.1210/en.2010-0434 ◽

2010 ◽

Vol 151 (10) ◽

pp. 4654-4664 ◽

Cited By ~ 12

Author(s):

Omar Flores ◽

Kerry L. Burnstein

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cell Cycle ◽

Vitamin D ◽

Androgen Receptor ◽

Growth Inhibition ◽

Cancer Cells ◽

Ectopic Expression ◽

Human Prostate Cancer ◽

Prostate Cancer Cells

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits proliferation of normal and malignant prostate epithelial cells at least in part through inhibition of G1 to S phase cell cycle progression. The mechanisms of the antiproliferative effects of 1,25-(OH)2D3 have yet to be fully elucidated but are known to require the vitamin D receptor. We previously developed a 1,25-(OH)2D3-resistant derivative of the human prostate cancer cell line, LNCaP, which retains active vitamin D receptors but is not growth inhibited by 1,25-(OH)2D3. Gene expression profiling revealed two novel 1,25-(OH)2D3-inducible genes, growth arrest and DNA damage-inducible gene gamma (GADD45γ) and mitogen induced gene 6 (MIG6), in LNCaP but not in 1,25-(OH)2D3-resistant cells. GADD45γ up-regulation was associated with growth inhibition by 1,25-(OH)2D3 in human prostate cancer cells. Ectopic expression of GADD45γ in either LNCaP or ALVA31 cells resulted in G1 accumulation and inhibition of proliferation equal to or greater than that caused by 1,25-(OH)2D3 treatment. In contrast, ectopic expression of MIG6 had only minimal effects on cell cycle distribution and proliferation. Whereas GADD45γ has been shown to be induced by androgens in prostate cancer cells, up-regulation of GADD45γ by 1,25-(OH)2D3 was not dependent on androgen receptor signaling, further refuting a requirement for androgens/androgen receptor in vitamin D-mediated growth inhibition. These data introduce two novel 1,25-(OH)2D3-regulated genes and establish GADD45γ as a growth-inhibitory protein in prostate cancer. Furthermore, the induction of GADD45γ gene expression by 1,25-(OH)2D3 may mark therapeutic response in prostate cancer.

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