Androgen receptors in early and castration resistant prostate cancer: friend or foe?

Pelekanou, Vassiliki; Notas, George; Stathopoulos, Efstathios N.; Castanas, Elias; Kampa, Marilena

doi:10.14310/horm.2002.1406

Cited by 14 publications

(18 citation statements)

References 94 publications

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“…They include Ca 2+ mobilization, PI3K/Akt, PLC, JNK and ERK1/2 activation2728. In addition, previous work429 established an intracellular rapid testosterone signaling, involving Ca 2+ mobilization, FAK, PI3K/Akt, and p38 MAPK30. Here, using a kinase array, we have examined the effect of testosterone-BSA and 5-OxoETE, in DU-145 cells.…”

Section: Resultsmentioning

confidence: 96%

“…AR dimerizes and translocates to the nucleus after androgen binding, affecting gene expression. However, during the last fifteen years, a large amount of evidence points out an alternative mode of androgen action, that is initiated at the cell membrane, involves rapid signaling via specific kinases and modulates a significant number of cellular processes4. Previous work demonstrated that membrane androgen sites are present in a number of physiological (T lymphocytes, macrophages, spermocytes, sperm, osteoblasts)567, and cancer cells (prostate, breast, colon)8910.…”

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confidence: 99%

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Antagonizing effects of membrane-acting androgens on the eicosanoid receptor OXER1 in prostate cancer

Kalyvianaki

Gebhart

Peroulis

et al. 2017

Sci Rep

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Accumulating evidence during the last decades revealed that androgen can exert membrane initiated actions that involve signaling via specific kinases and the modulation of significant cellular processes, important for prostate cancer cell growth and metastasis. Results of the present work clearly show that androgens can specifically act at the membrane level via the GPCR oxoeicosanoid receptor 1 (OXER1) in prostate cancer cells. In fact, OXER1 expression parallels that of membrane androgen binding in prostate cancer cell lines and tumor specimens, while in silico docking simulation of OXER1 showed that testosterone could bind to OXER1 within the same grove as 5-OxoETE, the natural ligand of OXER1. Interestingly, testosterone antagonizes the effects of 5-oxoETE on specific signaling pathways and rapid effects such as actin cytoskeleton reorganization that ultimately can modulate cell migration and metastasis. These findings verify that membrane-acting androgens exert specific effects through an antagonistic interaction with OXER1. Additionally, this interaction between androgen and OXER1, which is an arachidonic acid metabolite receptor expressed in prostate cancer, provides a novel link between steroid and lipid actions and renders OXER1 as new player in the disease. These findings should be taken into account in the design of novel therapeutic approaches in prostate cancer.

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Section: Resultsmentioning

confidence: 96%

mentioning

confidence: 99%

Antagonizing effects of membrane-acting androgens on the eicosanoid receptor OXER1 in prostate cancer

Kalyvianaki

Gebhart

Peroulis

et al. 2017

Sci Rep

Self Cite

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“…It has also been suggested that estrogen play a permissive role in androgen actions, since in their presence in culture media, DHEAS and androstenediol have antiproliferative effects in breast cancer, while in their absence the same molecules stimulate growth, an effect not observed with testosterone or DHT, that both inhibit cell proliferation independently of the presence of estrogen [60]. Most importantly, we have previously shown in T47D cells, that this effect is also dependent on non-genomic, membrane-initiated actions of androgen, triggering specific signaling cascades [61] since it can be reproduced with the use of membrane-impermeable BSA bound testosterone [62]. Therefore, the results of the in vitro androgen studies in the breast are highly dependent on the cell lines used, their ER status, the type/dose of the androgen used and factors yet unknown, due to our limited understanding of the mechanisms utilized by androgen in order to induce their effects.…”

Section: Discussionmentioning

confidence: 99%

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

Azariadis¹,

Kiagiadaki

Pelekanou³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. Methods: We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. Results: CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. Conclusion: AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors.

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“…Because normal prostate and prostate cancer cells are susceptible to androgen regulation (35), early prostate cancer can be controlled using androgen suppression. However, most prostate cancer patients develop androgen-independent prostate cancer (AIPC), which is very difficult to treat (36).…”

Section: Discussionmentioning

confidence: 99%

Downregulated expression of miRNA-149 promotes apoptosis in side population cells sorted from the TSU prostate cancer cell line

et al. 2016

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The objective of the present study was to identify prostate cancer stem cells and determine the effects of modulating specific miRNAs on prostate CSC proliferation and apoptosis. We applied flow cytometry sorting of side population cells to cultures of prostate cancer cell lines (TSU, DU145, PC-3 and LNCaP). The proportion of SP cells in the TSU line was 1.60±0.40% (mean ± SD), while that of the DU145, PC-3 and LNCaP lines was 0.60±0.05, 0.80±0.05 and 0.60±0.20%, respectively. Because the proportion of SP cells derived from TSU cells is greater, these cells were selected to sort side population cells and non-side population cells. The stem-like properties of SP cells had been identified by in vivo and in vitro experiments, and the related study was published. RNA was extracted from the SP cells and non-SP cells and analyzed using miRNA microarray technology. Fifty-three miRNAs with significant differences in their expression were detected in total. Furthermore, 20 of these miRNAs were validated by qPCR. We found that hsa-miR‑149 expression in SP cells and non-SP cells was significantly different; hsa-miR-149 was significantly upregulated in SP cells. By constructing a vector for lentiviral infection, we found that the downregulation of hsa-miR-149 leads to a reduction in proliferation, an increase in apoptosis, and a significant reduction in the colony formation potential, thus, inhibiting tumor growth in vivo of SP cells from the TSU cell line. The present study will provide new avenues toward understanding the function of prostate cancer stem cells (PCSCs) in tumorigenicity and metastasis.

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Androgen receptors in early and castration resistant prostate cancer: friend or foe?

Cited by 14 publications

References 94 publications

Antagonizing effects of membrane-acting androgens on the eicosanoid receptor OXER1 in prostate cancer

Antagonizing effects of membrane-acting androgens on the eicosanoid receptor OXER1 in prostate cancer

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

Downregulated expression of miRNA-149 promotes apoptosis in side population cells sorted from the TSU prostate cancer cell line

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