Changes in Androgen Receptor Nongenotropic Signaling Correlate with Transition of LNCaP Cells to Androgen Independence

Unni, Emmanual; Sun, Shihua; Nan, Bicheng; McPhaul, Michael J.; Cheskis, Boris J.; Mancini, Michael A.; Marcelli, Marco

doi:10.1158/0008-5472.can-04-1121

Cited by 207 publications

(185 citation statements)

References 71 publications

Supporting

Mentioning

173

Contrasting

Unclassified

Order By: Relevance

“…This, however, does not preclude the existence of one or more parallel PI3K-dependent pathways from AR to Akt (11,29). Because many hormone-resistant prostate cancers are AR-positive, our results suggest the possibility that membrane-associated AR may contribute to androgen-dependent growth of PCa cells in a manner that does not obligatorily involve the AR transcription function (39,49). Consistent with this idea, a cytoplasmic form of AR has recently been linked to human PCa metastasis (50).…”

Section: Discussionmentioning

confidence: 71%

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

Cinar

Mukhopadhyay

Meng

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The serine-threonine kinase, Akt1/protein kinase B␣ is an important mediator of growth, survival, and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft membranes as a potential site of intersection of androgenic and Akt1 signaling. A subpopulation of androgen receptor (AR) was found to localize to a lipid raft subcellular compartment in LNCaP prostate cancer cells. Endogenous AR interacted with endogenous Akt1 preferentially in lipid raft fractions and androgen substantially enhanced the interaction between the two proteins. The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K). Androgen promoted endogenous Akt1 activity in lipid raft fractions, in a PI3K-independent manner, within 10 min of treatment. Fusion of a lipid raft targeting sequence to AR enhanced localization of the receptor to rafts, and stimulated Akt1 activity in response to androgen, while reducing the cells' dependence on constitutive signaling through PI3K for cell survival. These findings suggest that signals channeled through AR and Akt1 intersect by a mechanism involving formation within lipid raft membranes of an androgen-responsive, extranuclear AR/Akt1 complex. Our results indicate that cholesterol-rich membrane microdomains play a role in transmitting nongenomic signals involving androgen and the Akt pathway in prostate cancer cells. Androgen receptor (AR),3 a member of the nuclear receptor superfamily of transcription factors, is an important regulator of reproductive physiology as a mediator of the biological activities of androgen (1). AR also plays a role in the pathogenesis of prostate cancer (PCa), including progression to the androgen-independent state and metastasis (2, 3). Upon androgen binding, the AR undergoes conformational changes and translocates from the cytosol to the nucleus (4), where the receptor-hormone complex regulates the expression of target genes (5).In addition to this well recognized genomic function, AR has been demonstrated to activate intracellular signaling pathways by a rapid (occurring in minutes) non-genomic process activated in response to hormonal stimulation (6, 7). The mechanisms underlying the non-canonical pathways involving the AR and other nuclear receptors are still poorly understood, however, possible nongenomic roles for the AR have been described (8 -12). For example, androgen promotes oocyte maturation, in both Xenopus (10) and mouse (12), by a transcription-independent mechanism that involves the classical AR (12,14). Another report showed that cells treated with 17␤-estradiol (E2) or androgen resulted in cell proliferation mediated by the rapid formation of a cytosolic signaling complex containing estrogen receptor-␣ or -␤ (ER␣ or ER␤ (depending on the cell type)), AR, and the non-receptor tyrosine kinase, Src (8). Similarly, Kousteni et al. (9) showed that ER␣, ER␤, or AR...

show abstract

Section: Discussionmentioning

confidence: 71%

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

Cinar

Mukhopadhyay

Meng

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Interestingly, we have observed that MED1 expression levels are amplified in a number of prostate cancer cell lines and clinically localized human prostate cancer specimens (34). Because MAPK-ERK signaling pathways are commonly constitutively activated in prostate cancer cells (52)(53)(54)(55)(56), especially the androgen-independent disease (53)(54)(55), it is plausible that hyperactivated MAPKs might promote MED1 overexpression during prostate oncogenesis. Indeed, our findings showing that activated ERK1/2 stabilizes MED1 protein expression in cultured prostate cancer cells is consistent with this hypothesis (Fig.…”

Section: Discussionmentioning

confidence: 97%

Regulation of Androgen Receptor-dependent Transcription by Coactivator MED1 Is Mediated through a Newly Discovered Noncanonical Binding Motif

Jin¹,

Claessens

Fondell³

2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: MED1 is a key coactivator for androgen receptor (AR)-dependent transcription in prostate cancer cells. Results: The mechanisms and binding motifs through which the MED1-Mediator complex functionally interact with AR were determined. Conclusion: MED1 functionally interacts with the Tau-1 domain of AR via a newly discovered noncanonical binding motif. Significance: Our findings provide new insights into the molecular mechanisms of AR-mediated transcriptional activation in prostate cancer cells.

show abstract

“…The association of AR with c-Src results in stimulation of c-Src kinase activity within 1 min in the LNCaP prostate cancer cell line [47]. Additionally, AR has been shown to complex with Src and the MNAR (modulator of non-genomic action of estrogen receptor) protein [63]. In prostate cancer cells, AR/Src/MNAR association and the resulting MAPK activation has been shown to be both androgen dependent and independent [63].…”

Section: Androgens Activate Second Messenger Pathwaysmentioning

confidence: 99%

“…Additionally, AR has been shown to complex with Src and the MNAR (modulator of non-genomic action of estrogen receptor) protein [63]. In prostate cancer cells, AR/Src/MNAR association and the resulting MAPK activation has been shown to be both androgen dependent and independent [63]. One of the targets of c-Src is the adapter protein Shc, an upstream regulator of the MAPK pathway.…”

Section: Androgens Activate Second Messenger Pathwaysmentioning

confidence: 99%

Non-genomic actions of androgens

Foradori

Weiser

Handa

2008

Frontiers in Neuroendocrinology

407

244

View full text Add to dashboard Cite

Previous work in the endocrine and neuroendocrine fields has viewed androgen receptors (AR) as a transcription factor activated by testosterone or one of its many metabolites. The bound androgen receptor acts as transcription factor and binds to specific DNA response elements in target gene promoters, causing activation or repression of transcription and subsequently protein synthesis. Over the past two decades evidence has begun to accumulate to implicate androgens, dependent or independent of the AR, in rapid actions at the cellular and organism level. Androgen's rapid time course of action; effects in the absence or inhibition of the cellular machinery necessary for transcription/translation; and/or the effects of androgens not able to translocate to the nucleus suggest a method of androgen action not initially dependent on genomic mechcanisms (i.e. non-genomic in nature). In the present paper the non-genomic effects of androgens are reviewed, along with a discussion of the possible role non-genomic androgen actions have on animal physiology and behavior.

show abstract

Changes in Androgen Receptor Nongenotropic Signaling Correlate with Transition of LNCaP Cells to Androgen Independence

Cited by 207 publications

References 71 publications

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

Regulation of Androgen Receptor-dependent Transcription by Coactivator MED1 Is Mediated through a Newly Discovered Noncanonical Binding Motif

Non-genomic actions of androgens

Contact Info

Product

Resources

About