Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence

The Prostate ◽  
2008 ◽  
Vol 68 (7) ◽  
pp. 698-714 ◽  
Author(s):  
Jason M. D'Antonio ◽  
Changqing Ma ◽  
Federico A. Monzon ◽  
Beth R. Pflug
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Longitudinal Analysis ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Androgen Independence

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 MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

PLoS Genetics ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. e1008540
Author(s):  
Hannah Weber ◽  
Rachel Ruoff ◽  
Michael J. Garabedian
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Cells ◽  
Androgen Deprivation ◽  
Monoamine Oxidase A ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Cancer Cell Growth ◽  
Androgen Independence ◽  
Androgen Independent

Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19-overexpressing LNCaP cells. We also examined genome-wide H3K27 acetylation. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation, and genomic sites occupied by MED19 and AR are enriched for motifs associated with ELK1. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.

STEM CELL MARKERS ARE UP REGULATED IN PROSTATE CANCER CELLS BY ANDROGEN DEPRIVATION DURING PROGRESSION TOWARDS ANDROGEN INDEPENDENCE

2009 ◽  
Vol 181 (4S) ◽  
pp. 480-481
Author(s):  
Markus Germann ◽  
Marco G Cecchini ◽  
Urs E Studer ◽  
George N Thalmann
Keyword(s):  
Prostate Cancer ◽  
Stem Cell ◽  
Cancer Cells ◽  
Androgen Deprivation ◽  
Stem Cell Markers ◽  
Prostate Cancer Cells ◽  
Androgen Independence ◽  
Cell Markers

Androgen-deprivation induced senescence in prostate cancer cells is permissive for the development of castration-resistance but susceptible to senolytic therapy

2021 ◽  
Vol 193 ◽  
pp. 114765
Author(s):  
Valerie Carpenter ◽  
Tareq Saleh ◽  
So Min Lee ◽  
Graeme Murray ◽  
Jason Reed ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Androgen Deprivation ◽  
Castration Resistance ◽  
Prostate Cancer Cells

scholarly journals Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

Oncotarget ◽  
2014 ◽  
Vol 5 (19) ◽  
pp. 9335-9348 ◽  
Author(s):  
Andressa Ardiani ◽  
Sofia R. Gameiro ◽  
Anna R. Kwilas ◽  
Renee N. Donahue ◽  
James W. Hodge
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
T Cell ◽  
Cancer Cells ◽  
Androgen Deprivation Therapy ◽  
Cell Killing ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Apoptotic Pathway

scholarly journals Persistence of senescent prostate cancer cells following prolonged neoadjuvant androgen deprivation therapy

PLoS ONE ◽  
2017 ◽  
Vol 12 (2) ◽  
pp. e0172048 ◽  
Author(s):  
Michael L. Blute ◽  
Nathan Damaschke ◽  
Jennifer Wagner ◽  
Bing Yang ◽  
Martin Gleave ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells

scholarly journals Prolonged androgen deprivation leads to downregulation of androgen receptor and prostate-specific membrane antigen in prostate cancer cells

2012 ◽  
Vol 41 (6) ◽  
pp. 2087-2092 ◽  
Author(s):  
TIANCHENG LIU ◽  
LISA Y. WU ◽  
MELODY D. FULTON ◽  
JACQUELINE M. JOHNSON ◽  
CLIFFORD E. BERKMAN
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Androgen Deprivation ◽  
Prostate Specific Membrane Antigen ◽  
Prostate Cancer Cells ◽  
Specific Membrane

scholarly journals Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation

2016 ◽  
Vol 22 (13) ◽  
pp. 3310-3319 ◽  
Author(s):  
Mohammad Hedayati ◽  
Michael C. Haffner ◽  
Jonathan B. Coulter ◽  
Raju R. Raval ◽  
Yonggang Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ionizing Radiation ◽  
Cancer Cells ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells

scholarly journals PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 3
Author(s):  
Magali Williamson ◽  
Ritu Garg ◽  
Claire M. Wells
Keyword(s):  
Prostate Cancer ◽  
Glucocorticoid Receptor ◽  
Cancer Cells ◽  
Androgen Deprivation Therapy ◽  
Late Stage ◽  
Nuclear Translocation ◽  
Androgen Deprivation ◽  
Nuclear Localization Sequence ◽  
Prostate Cancer Cells ◽  
Localization Sequence

Androgen receptor (AR) and glucocorticoid receptor (GR) are nuclear receptors whose function depends on their entry into the nucleus where they activate transcription of an overlapping set of genes. Both AR and GR have a role in resistance to androgen deprivation therapy (ADT), the mainstay of treatment for late stage prostate cancer. PlexinB1, a receptor for semaphorins, has been implicated in various cancers including prostate cancer and has a role in resistance to ADT. We show here that activation of PlexinB1 by Sema4D and Sema3C results in translocation of endogenous GR to the nucleus in prostate cancer cells, and that this effect is dependent on PlexinB1 expression. Sema4D/Sema3C promotes the translocation of GR-GFP to the nucleus and mutation of the nuclear localization sequence (NLS1) of GR abrogates this response. These findings implicate the importin α/β system in the Sema4D/Sema3C-mediated nuclear import of GR. Knockdown of PlexinB1 in prostate cancer cells decreases the levels of glucocorticoid-responsive gene products and antagonizes the decrease in cell motility and cell area of prostate cancer cells upon dexamethasone treatment, demonstrating the functional significance of these findings. These results show that PlexinB1 activation has a role in the trafficking and activation of the nuclear receptor GR and thus may have a role in resistance to androgen deprivation therapy in late stage prostate cancer.

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