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

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.

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

PLoS ONE ◽

10.1371/journal.pone.0172048 ◽

2017 ◽

Vol 12 (2) ◽

pp. e0172048 ◽

Cited By ~ 7

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

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

International Journal of Oncology ◽

10.3892/ijo.2012.1649 ◽

2012 ◽

Vol 41 (6) ◽

pp. 2087-2092 ◽

Cited By ~ 27

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

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PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor

Cells ◽

10.3390/cells9010003 ◽

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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Regenerated Luminal Epithelial Cells Are Derived from Preexisting Luminal Epithelial Cells in Adult Mouse Prostate

Molecular Endocrinology ◽

10.1210/me.2011-1081 ◽

2011 ◽

Vol 25 (11) ◽

pp. 1849-1857 ◽

Cited By ~ 60

Author(s):

June Liu ◽

Laura E. Pascal ◽

Sudhir Isharwal ◽

Daniel Metzger ◽

Raquel Ramos Garcia ◽

...

Keyword(s):

Prostate Cancer ◽

Epithelial Cells ◽

Cancer Cells ◽

Androgen Deprivation Therapy ◽

Specific Antigen ◽

Androgen Deprivation ◽

Genetic Lineage ◽

Prostate Cancer Cells ◽

Mouse Prostate ◽

Luminal Epithelial Cells

Abstract Determining the source of regenerated luminal epithelial cells in the adult prostate during androgen deprivation and replacement will provide insights into the origin of prostate cancer cells and their fate during androgen deprivation therapy. Prostate stem cells in the epithelial layer have been suggested to give rise to luminal epithelium. However, the extent of stem cell participation to prostate regrowth is not clear. In this report, using prostate-specific antigen-CreERT2-based genetic lineage marking/tracing in mice, preexisting luminal epithelial cells were shown to be a source of regenerated luminal epithelial cells in the adult prostate. Prostatic luminal epithelial cells could survive androgen deprivation and were capable of proliferating upon androgen replacement. Prostate cancer cells, typically exhibiting a luminal epithelial phenotype, may retain this intrinsic capability to survive and regenerate in response to changes in androgen signaling, providing part of the mechanism for the ultimate failure of androgen deprivation therapy in prostate cancer.

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