Membrane androgen receptor activation triggers down-regulation of PI-3K/Akt/NF-kappaB activity and induces apoptotic responses via Bad, FasL and caspase-3 in DU145 prostate cancer cells

Papadopoulou, Natalia; Charalampopoulos, Ioannis; Anagnostopoulou, Vasileia; Konstantinidis, Georgios; Föller, Michael; Gravanis, Achilleas; Alevizopoulos, Konstantinos; Läng, Florian; Stournaras, Christos

doi:10.1186/1476-4598-7-88

Cited by 58 publications

(52 citation statements)

References 45 publications

(68 reference statements)

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“…In the presence or absence of 10 26 mol l 21 wortmannin (Sigma), they were stimulated in serum containing medium with 10 27 mol l 21 of testosterone-HSA for 12 h. Untreated cells cultured in serum free medium were used as positive control for the apoptotic response.After the indicated time periods, medium was discarded, and apoptosis was assayed using the APOPercentage Apoptosis Assay kit (Biocolor Ltd), as previously described. 9 The assay uses a dye which is imported by cells undergoing apoptosis, when the 'flip-flop' mechanism translocate phosphatidylserine to the outer membrane leaflet. The dye has a purple-red color.…”

Section: Rac1 Activation Assaymentioning

confidence: 99%

“…[2][3][4][5][6][7] Activation of these binding sites by no permeable testosterone albumin conjugates (TACs), was shown to induce strong proapoptotic and anti-tumorigenic effects on various tumors both in vitro and in vivo. 2,6,8,9 The molecular mechanisms governing these effects have been elucidated and specific signaling cascades triggered by the stimulation of membrane androgen receptors (mARs) have been described in prostate and breast tumor cells. 4,5,[9][10][11] Functional membrane androgen binding sites have been also reported in colon cancer cells and tissues.…”

Section: Introductionmentioning

confidence: 99%

“…2,6,8,9 The molecular mechanisms governing these effects have been elucidated and specific signaling cascades triggered by the stimulation of membrane androgen receptors (mARs) have been described in prostate and breast tumor cells. 4,5,[9][10][11] Functional membrane androgen binding sites have been also reported in colon cancer cells and tissues. 12,13 Their activation by testosterone conjugates induced potent pro-apoptotic responses.…”

Section: Introductionmentioning

confidence: 99%

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Testosterone induced apoptosis in colon cancer cells is regulated by PI3K/Rac1 signaling

Alkahtani¹

2013

Asian J Androl

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Recently, it has been reported that testosterone membrane signaling regulates actin reorganization and induces pro-apoptotic responses in colon tumor cells. In the present study the membrane androgen receptors (mARs)-induced activation of Rac1 GTPase and the involvement of PI3K/Rac1 signaling in controlling the apoptotic responses in testosterone treated Caco2 colon cancer cells has been analyzed. In line with previous findings, activation of mAR by testosterone conjugates triggered early and transient actin reorganization as indicated by the significant decrease of the G/Total actin ratio after 15-and 30-min treatment of the cells. Interestingly, stimulation of mAR rapidly activated the Rac1 GTPase. This effect was evident after 15 min and persisted for at least 24 h. Testosterone induced Rac1 activation was fully blocked in Caco2 cells pre-treated with the PI3K inhibitor wortmannin, indicating that Rac1 signaling is acting downstream of the PI3K pathway. Remarkably, when cells were pre-treated with wortmannin that blocks the PI3K/Rac1 signaling, apoptotic response was almost fully inhibited. These finding suggest that Rac1 activation, triggering actin redistribution, is involved in testosterone induced pro-apoptotic responses governed by mAR activation and emphasize the regulatory role of PI3K/Rac1 signaling in colon tumors.

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Section: Rac1 Activation Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Testosterone induced apoptosis in colon cancer cells is regulated by PI3K/Rac1 signaling

Alkahtani¹

2013

Asian J Androl

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“…Indeed, long term down regulation of the pro-survival PI-3K/Akt pathway became evident 12-24 h upon mAR activation as indicated by the significant decrease of the phosphorylation levels of PI-3K and Akt. Furthermore, inhibition of NF-jB translocation and increased FasL expression were documented, while increased caspase 3 activity was measured (38). These events were regulated by mAR-induced Rho/ ROCK/actin signaling, as indicated either by transfection experiments with dominant negative mutants or by pharmacological inhibitors of this pathway.…”

Section: Membrane Androgen Receptor Signaling In Human Cancer Cells Mmentioning

confidence: 99%

Membrane androgen receptor activation in prostate and breast tumor cells: Molecular signaling and clinical impact

et al. 2008

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In recent years, membrane androgen receptors (mARs) have been identified in prostate and breast tumor cells, and their activation by specific mAR ligands was linked to the regulation of crucial cell responses, such as cell growth, motility, and apoptosis. Analysis of the molecular signals triggered by mAR in the presence of anti‐androgens has clearly differentiated mAR‐dependent biological actions from those induced by the activation of the classical intracellular androgen receptors (iARs). In this review, we summarize the specific cellular events attributed to mAR activation and the experimental results on distinct non‐genomic signaling cascades operating in various tumor cells independently of the iAR. Furthermore, we discuss the crucial role of actin cytoskeleton organization and signaling in mediating mAR responses. Finally, we assess the clinical impact of the reported mAR‐induced apoptotic regression of prostate cancer cells both in vitro and in vivo and discuss the potential role of mAR as a novel therapeutic target. © 2008 IUBMB IUBMB Life, 61(1): 56–61, 2009

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“…The mAR-dependent nongenomic signaling was recently characterized in detail in prostate and breast cancer cells (15), and key prosurvival and proapoptotic gene products were identified that regulate the apoptotic response induced by mAR activation (16). According to these reports it was postulated that mAR might be a significant novel target for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Activation of Membrane Androgen Receptors in Colon Cancer Inhibits the Prosurvival Signals Akt/Bad In Vitro and In Vivo and Blocks Migration via Vinculin/Actin Signaling

Papadopoulou

Nasir

et al. 2010

Mol Med

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Recently, we reported that membrane androgen receptors (mARs) are expressed in colon tumors triggering strong apoptotic responses. In the present study, we analyzed mAR-induced downstream effectors controlling cell survival and migration of Caco2 colon cancer cells. We show that long-term activation of mAR downregulated the activity of PI-3K and Akt and induced dephosphorylation/activation of the proapoptotic Bad (p-Bad). Moreover, treatment of APC Min/+ mice, which spontaneously develop intestinal tumors, with mAR-activating testosterone conjugates reduced the tumor incidence by 80% and significantly decreased the expression of p-Akt and p-Bad levels in tumor tissue. Furthermore, mAR activation strongly inhibited Caco2 cell migration. In accordance with these findings, vinculin, a protein controlling cell adhesion and actin reorganization, was effectively phosphorylated upon mAR activation. Phosphorylation inhibitors genistein and PP2 inhibited actin reorganization and restored motility. Moreover, silencing vinculin by appropriate siRNA's, or blocking actin reorganization by cytochalasin B, restored the migration potential. From these results we conclude that mAR activation inhibits the prosurvival signals Akt/Bad in vitro and in vivo and blocks migration of colon cancer cells via regulation of vinculin signaling and actin reorganization, supporting the powerful tumoristatic effect of those receptors.

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Membrane androgen receptor activation triggers down-regulation of PI-3K/Akt/NF-kappaB activity and induces apoptotic responses via Bad, FasL and caspase-3 in DU145 prostate cancer cells

Cited by 58 publications

References 45 publications

Testosterone induced apoptosis in colon cancer cells is regulated by PI3K/Rac1 signaling

Testosterone induced apoptosis in colon cancer cells is regulated by PI3K/Rac1 signaling

Membrane androgen receptor activation in prostate and breast tumor cells: Molecular signaling and clinical impact

Activation of Membrane Androgen Receptors in Colon Cancer Inhibits the Prosurvival Signals Akt/Bad In Vitro and In Vivo and Blocks Migration via Vinculin/Actin Signaling

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