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Autor     Natalia Papadopoulou, Evangelia A. Papakonstanti, Galatea Kallergi, Konstantinos Alevizopoulos and Christos Stournaras
Titel    Membrane Androgen Receptor Activation in Prostate and Breast Tumor Cells: Molecular Signaling and Clinical Impact
Zeitschrift    IUBMB Life
Datum    January 2009
Seiten    56–61
ISSN    1521-6551
DOI    10.1002/iub.150
URL    http://onlinelibrary.wiley.com/doi/10.1002/iub.150/pdf

Literaturverz.   

ja
Fußnoten    ja
Fragmente    3


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[1.] Shg/Fragment 017 15 - Diskussion
Zuletzt bearbeitet: 2014-11-01 21:20:28 Hindemith
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In prostate cancer, expression of mAR in human tumor cells was initially reported in iAR positive LNCaP cells [Kampa M, et al 2002] and iAR –deficient DU145 cells [Hatzoglou A, et al 2005]. In LNCaP cells study, mAR activation through testosterone-BSA conjugates induced rapid PSA release, fast actin reorganization and additional cell responses like inhibition of cell growth and induction of apoptosis [Hatzoglou A, et al 2005]. The molecular signaling pathway starts from focal adhesion kinase (FAK). Initially, FAK was rapidly phosphorylated and associated with the p85 subunit of the phosphoinositol-3-Kinase (PI-3K). Following this association, the lipid kinase activity of PI-3K and the tyrosine phosphorylation of its p85 regulatory subunit were significantly induced by mAR stimulation. PI-3K activation was accompanied by the downstream upregulation of the Rho small GTPases Cdc42, Rac1, RhoA and RhoB. Rapid activation of these GTPases resulted in actin cytoskeleton reorganization. Yet again, these effects were specific for mAR because three different steroidal and non-steroidal iAR antagonists failed to block the activation of this rapid signaling pathway [Papakonstanti, E. A., et al. 2003]. From these findings it was concluded that mAR activation induced potent apoptotic regression in LNCaP prostate tumor cells controlled by [Rho/ROCK/actin signaling.]

Kampa M, Papakonstanti EA, Hatzoglou A, Stathopoulos EN, Stournaras C, Castanas E. (2002). The human prostate cancer cell line LNCaP bears functional membrane testosterone receptors that increase PSA secretion and modify actin cytoskeleton. Faseb J, 16:1429-1431.

Hatzoglou A, Kampa M, Kogia C, Charalampopoulos I, Theodoropoulos PA, Anezinis P, Dambaki C, Papakonstanti EA, Stathopoulos EN, Stournaras C, et al. (2005). Membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo. J Clin Endocrinol Metab, 90: 893-903.

Papakonstanti, E. A., Kampa, M., Castanas, E., and Stournaras, C. (2003). A rapid, nongenomic, signaling pathway regulates the actin reorganization induced by activation of membrane testosterone receptors. Mol. Endocrinol. 17, 870–881.

Expression of mAR in human tumor cells was initially reported in iAR positive LNCaP cells (9). In this study, mAR activation through testosterone, dihydrotestosterone (DHT) or TBSA conjugates induced rapid PSA release and potent and fast actin reorganization. Subsequent studies analyzed additional cell responses triggered by mAR stimulation including mAR-dependent inhibition of cell growth and induction of apoptosis (21). [...] Analysis of the molecular signaling activated by mAR identified a novel mAR-specific non-genomic pathway operating in LNCaP cells (25, 34). Initially, focal adhesion kinase (FAK) was rapidly phosphorylated and associated with the p85 subunit of the phosphoinositol-3-Kinase (PI-3K). Following this association, the lipid kinase activity of PI-3K and the tyrosine phosphorylation of its p85 regulatory subunit were significantly induced by mAR stimulation. PI-3K activation was accompanied by the downstream upregulation of the Rho small GTPases Cdc42, Rac1, RhoA and RhoB. Rapid activation of these GTPases resulted in actin cytoskeleton reorganization. Yet again, these effects were specific for mAR because three different steroidal and non-steroidal iAR antagonists failed to block the activation of this rapid signaling pathway (25). [...] From these findings it was concluded that mAR activation induces potent apoptotic regression in LNCaP prostate tumor cells controlled by Rho/ROCK/actin signaling.

9. Kampa, M., Papakonstanti, E. A., Hatzoglou, A., Stathopoulos, E. N., Stournaras, C., and Castanas, E. (2002) The human prostate cancer cell line LNCaP bears functional membrane testosterone receptors that increase PSA secretion and modify actin cytoskeleton. Faseb. J. 16, 1429–1431.

21. Hatzoglou, A., Kampa, M., Kogia, C., Charalampopoulos, I., Theodoropoulos, P. A., Anezinis, P., Dambaki, C., Papakonstanti, E. A., Stathopoulos, E. A., Stournaras, C., Gravanis, A., and Castanas E. (2005) Membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo. J. Clin. Endocrinol. Metab. 90, 893–903.

25. Papakonstanti, E. A., Kampa, M., Castanas, E., and Stournaras, C. (2003) A rapid, nongenomic, signaling pathway regulates the actin reorganization induced by activation of membrane testosterone receptors. Mol. Endocrinol. 17, 870–881.

34. Papadopoulou, N., Charalampopoulos, I., Alevizopoulos, K., Gravanis, A., and Stournaras, C. 2008. Rho/ROCK/Actin signaling regualtes membrane androgen receptor induced apoptosis in prostate cancer cells. Exp. Cell. Res., 314, 3162–3174.

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[2.] Shg/Fragment 018 01 - Diskussion
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Interestingly, while LNCaP prostate cancer cells express functional iAR, the DU145 cell line expresses either nonfunctional iAR, or is iAR-deficient. Therefore, DU145 cells fail to respond to iAR-regulated androgen treatment.[ Alimirah, F., et al 2006] In this cell model, mAR stimulation by testosterone or T-BSA conjugates induced potent actin reorganization, inhibited cell motility and promoted apoptotic regression. [Papadopoulou N, et al. 2008a] But the signaling pathway is different from LNCaP cells. Specifically, mAR activation bypassed the FAK/ PI-3K signaling pathway, as FAK was shown to be constitutively phosphorylated and mAR stimulation failed to further activate the downstream effectors PI-3K and Rac. An alternative pathway functionally distinct from the FAK/PI-3K/Rac signaling was described. [Papadopoulou N, et al. 2008a] This pathway regulated actin reorganization, the induction of apoptosis and the pro-apoptotic machinery. 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-jkB translocation and increased FasL expression were documented, while increased caspase 3 activity was measured [Papadopoulou N, et al 2008b].

Shg 018ab diss.png

Figure 3: mAR signaling in human prostate cancer cells

A) Non-genomic mAR signaling operating in iAR positive LNCaP human prostate cancer cells regulating actin redistribution and apoptosis. Solid arrows indicate events that have been experimentally proven. Dashed arrows indicate unidentified possible links. See text for details.

B) Early and late mAR signaling operating in iAR deficient DU145 human prostate cancer cells regulating actin redistribution, downstream pro-apoptotic signaling, and migration. Solid arrows [indicate events that have been experimentally proven. Dashed arrows indicate unidentified possible links. See text for details. [Papadopoulou N, et al 2009]]


Alimirah, F., Chen, J., Basrawala, Z., Xin, H., and Choubey, D. (2006). DU-145 and PC-3 human prostate cancer cell lines express androgen receptor: implications for the androgen receptor functions and regulation. FEBS. Lett. 580, 2294–2300

Papadopoulou N, Charalampopoulos I, Alevizopoulos K, Gravanis A, Stournaras C. (2008 a). Rho/ROCK/Actin signaling regualtes membrane androgen receptor induced apoptosis in prostate cancer cells. Exp Cell Res, 314: 3162-3174.

Papadopoulou N, Charalampopoulos I, Anagnostopoulou V, Konstantinidis G, Föller M, Gravanis A, Alevizopoulos K, Lang F, Stournaras C. (2008 b). 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 DU-145 prostate cancer cells. Mol Canc. 7:88.

[Page 57]

mAR Signaling in iAR-Deficient DU145 Prostate Cancer Cells

mAR expression was also reported in iAR-deficient DU145 prostate cancer cells (21). Interestingly, while LNCaP prostate cancer cells express functional intracellular androgen receptors (iAR), the DU145 cell line expresses either nonfunctional iAR (35), or is iAR-deficient (36, 37). Therefore, DU145 cells fail to respond to iAR-regulated androgen treatment (35). In this cell model, mAR stimulation by testosterone or T-BSA conjugates induced potent actin reorganization, inhibited cell motility and promoted apoptotic regression (21, 34). mAR signaling in DU145 cells was recently analyzed providing some very interesting results. Specifically, mAR activation bypassed the FAK/ PI-3K signaling pathway, as FAK was shown to be constitutively phosphorylated and mAR stimulation failed to further activate the downstream effectors PI-3K and Rac1. An alternative pathway functionally distinct from the FAK/PI-3K/Rac signaling was described. [...]. Functional analysis of the pathway revealed that Rho/ROCK signaling regulated, besides actin reorganization, the induction of apoptosis and the pro-apoptotic machinery. 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).

[Page 58]

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Figure 1. Non-genomic mAR signaling operating in iAR positive LNCaP human prostate cancer cells regulating actin redistribution and apoptosis. Solid arrows indicate events that have been experimentally proven. Dashed arrows indicate unidentified possible links. See text for details.

Shg 018b source.png

Figure 2. Early and late mAR signaling operating in iAR deficient DU145 human prostate cancer cells regulating actin redistribution, downstream pro-apoptotic signaling, and migration. Solid arrows indicate events that have been experimentally proven. Dashed arrows indicate unidentified possible links. See text for details.



21. Hatzoglou, A., Kampa, M., Kogia, C., Charalampopoulos, I., Theodoropoulos, P. A., Anezinis, P., Dambaki, C., Papakonstanti, E. A., Stathopoulos, E. A., Stournaras, C., Gravanis, A., and Castanas E. (2005) Membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo. J. Clin. Endocrinol. Metab. 90, 893–903.

34. Papadopoulou, N., Charalampopoulos, I., Alevizopoulos, K., Gravanis, A., and Stournaras, C. 2008. Rho/ROCK/Actin signaling regualtes membrane androgen receptor induced apoptosis in prostate cancer cells. Exp. Cell. Res., 314, 3162–3174.

35. Alimirah, F., Chen, J., Basrawala, Z., Xin, H., and Choubey, D. (2006) DU-145 and PC-3 human prostate cancer cell lines express androgen receptor: implications for the androgen receptor functions and regulation. FEBS. Lett. 580, 2294–2300.

36. Stone, K. R., Mickey, D. D., Wunderli, H., Mickey, G. H., and Paulson, D. F. (1978) Isolation of a human prostate carcinoma cell line (DU 145). Int. J. Cancer. 21, 274–281.

37. Mitchell, S., Abel, P., Ware, M., Stamp, G., and Lalani, E. (2000) Phenotypic and genotypic characterization of commonly used human prostatic cell lines. BJU. Int. 85, 932–944.

38. Papadopoulou, N., Charalampopoulos, I., Anagnostopoulou, V., Konstandinidis, G., Foeller, M., Gravanis, A., Alevizopoulos, K., Lang, F., and Stournaras, C. Membrane androgen receptor activation triggers down-regulation of PI-3K/AKT/NF-κB activity and induces apoptotic responses via Bad, FasL and caspase 3 in DU-145 prostate cancer cells, Submitted.

Anmerkungen

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Papadopoulou et al. (2008b) does not contain the copied text.

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[3.] Shg/Fragment 019 01 - Diskussion
Zuletzt bearbeitet: 2014-11-02 08:51:00 Hindemith
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[Solid arrows] indicate events that have been experimentally proven. Dashed arrows indicate unidentified possible links. See text for details. [Papadopoulou N, et al 2009]

In breast cancer, it has been reported that mAR is expressed in T47D and MCF7 human breast epithelial cancer cells. In T47D cells, specific and saturable androgen receptors are present in the membrane and their activation via TBSA conjugates resultes [sic] in cell death by apoptosis. [Kampa M, et al 2005] Moreover, pharmacological inhibitors of MEK and p38 kinase were able to block T-BSA induced apoptosis showing a functional implication of these pathways in mAR-dependent apoptosis in T47D cells. However, in MCF7 cells, activation of these receptors by T-BSA conjugates triggered a non-genomic signaling pathway involving FAK and PI-3K phosphorylation and downstream activation of the small GTPase Rac1, ultimately resulting in actin redistribution. Cell migration experiments provided insights in the functional role of mAR stimulation in MCF7 cells. But the activations of mAR did not induce any apoptotic response in this kind of cells. [Kallergi G, et a.l 2007]

Shg 019a diss.png

Figure 4: mAR signaling in breast epithelial cancer cells

Non-genomic mAR signaling operating in MCF7 breast epithelial cancer cells regulating actin redistribution and cell motility. Solid arrows indicate events that have been experimentally proven. Dashed arrows indicate unidentified possible links. [Papadopoulou N, et al 2009]


Papadopoulou N, Papakonstanti EA, Kallergi G, Alevizopoulos K, Stournaras C. (2009). Membrane androgen receptor activation in prostate and breast tumor cells: Molecular signaling and clinical impact. IUBMB Life, 61(1): 56-61.

Kampa M, Nifli AP, Charalampopoulos I, Alexaki VI, Theodoropoulos PA, Stathopoulos EN, Gravanis A, Castanas E. (2005). Opposing effects of estradiol- and testosterone-membrane binding sites on T47D breast cancer cell apoptosis. Exp Cell Res, 307:41-51.

Kallergi G, Agelaki S, Markomanolaki H, Georgoulias V, Stournaras C. (2007). Activation of FAK/PI3K/Rac1 signaling controls actin reorganization and inhibits cell motility in human cancer cells. Cell Physiol Biochem, 20:977-986.

Figure 2. Early and late mAR signaling operating in iAR deficient DU145 human prostate cancer cells regulating actin redistribution, downstream pro-apoptotic signaling, and migration. Solid arrows indicate events that have been experimentally proven. Dashed arrows indicate unidentified possible links. See text for details.

Shg 019a source.png

Figure 3. Non-genomic mAR signaling operating in MCF7 breast epithelial cancer cells regulating actin redistribution and cell motility. Solid arrows indicate events that have been experimentally proven. Dashed arrows indicate unidentified possible links. See text for details.

Besides prostate cancer cells, mAR expression has recently been reported in T47D and MCF7 human breast epithelial cancer cells. In T47D cells, specific and saturable androgen receptors are present in the membrane and their activation via TBSA conjugates resulted in cell death by apoptosis (15). [...] Moreover, pharmacological inhibitors of MEK and p38 kinase were able to block T-BSA induced apoptosis showing a functional implication of these pathways in mAR-dependent apoptosis in T47D cells. In another recent study, we have reported the expression of mAR in MCF7 cells (20). Activation of these receptors by T-BSA conjugates triggered a non-genomic signaling pathway involving FAK and PI-3K phosphorylation and downstream activation of the small GTPase Rac1, ultimately resulting in actin redistribution. [...] Cell migration experiments provided insights in the functional role of mAR stimulation in MCF7 cells. [...]



15. Kampa, M., Nifli, A. P., Charalampopoulos, I., Alexaki, V. I., Theodoropoulos, P.A., Stathopoulos, E.N., Gravanis, A., and Castanas, E. (2005) Opposing effects of estradiol- and testosterone-membrane binding sites on T47D breast cancer cell apoptosis. Exp. Cell. Res. 307, 41–51.

20. Kallergi, G., Agelaki, S., Markomanolaki, H., Georgoulias, V., and Stournaras, C. (2007) Activation of FAK/PI3K/Rac1 signaling controls actin reorganization and inhibits cell motility in human cancer cells. Cell. Physiol. Biochem. 20, 977–986.

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