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Untersuchte Arbeit:
Seite: 75, Zeilen: 1-28
Quelle: Gu et al 2009
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[Moreover,] membrane-impermeable testosterone albumin conjugates induce considerable apoptosis via activation of the pro-apoptotic executor caspase-3. [Gu S, et al. 2009] The observed mAR-activated effects are specific and independent from the classical intracellular androgen receptors (iAR), since they were manifested in the presence of the anti-androgen flutamide. In addition, mAR staining could be also detected in iAR silenced Caco2 cells (Fig 6B) and iAR-deficient DU145 human prostate cancer cells [Hatzoglou A, et al. 2005]. All those imply that the molecular identity of mAR is probably not identical with iAR, targeted to the plasma membrane.

5.1 Membrane androgen receptor activation in colon cancer triggers pro-apoptotic responses in vitro and in vivo

The results from my diplom thesis have show that membrane-impermeable testosterone albumin conjugates induced considerable apoptosis via activation of the pro-apoptotic executor caspase-3. Moreover, the results from other studies indicated as well that membrane androgen receptors are predominantly expressed in tumor cells. Activation of these receptors triggers pro-apoptotic responses. One possible rationalization for the expression of those receptors is that tumor cells may compensate mAR-dependent apoptosis by over-expressing anti-apoptotic proteins or other compensatory mechanisms that collectively protect against mAR-dependent pro-apoptotic effects. Previous reports support this assumption: Indeed, iAR deficient DU145 human prostate cancer cells were shown to over-express the pro-survival PI-3K/Akt pathway, which was down-regulated following long-term mAR activation [Papadopoulou N, et al. 2008A]. In addition, the FAK/PI3K pathway was constitutively activated in DU145 cells and mAR activation was unable to further alter the short-term phosphorylation levels of those kinases [Papadopoulou N, et al. 2008], while long term activation induced significant de-phosphorylation [Papadopoulou N, et al. 2008A].


Gu S, Papadopoulou N, Gehring EM, Nasir O, Dimas K, Bhavsar SK, Foller M, Alevizopoulos K, Lang F, Stournaras C. (2009) Functional membrane androgen receptors in colon tumors trigger pro-apoptotic responses in vitro and reduce drastically tumor incidence in vivo. Mol Cancer. 8:114.

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.

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.

Moreover, membrane-impermeable testosterone albumin conjugates induced a) profound and rapid actin and tubulin reorganization, and b) considerable apoptosis via activation of the pro-apoptotic executor caspase-3. The observed mAR-activated effects were specific for testosterone and testosterone conjugates, since other steroid hormones such as estradiol did not exhibit any pro-apoptotic activity.

(Fig 5A, B), imply that the molecular identity of mAR is probably not identical with iAR, targeted to the plasma membrane.

The results from this and other studies indicated that membrane androgen receptors are predominantly expressed in tumor cells ([31] and Fig. 2B, 7B). In addition, activation of these receptors triggers pro-apoptotic responses. One possible rationalization for the expression of those receptors is that tumor cells may compensate mAR-dependent apoptosis by over-expressing anti-apoptotic proteins or other compensatory mechanisms that collectively protect against mAR-dependent apoptosis. Previous reports support this assumption: Indeed, iARdeficient DU145 human prostate cancer cells were shown to overexpress the pro-survival PI-3K/Akt pathway, which was down-regulated following long-term mAR activation [9]. In addition, the FAK/PI3K pathway was constitutively activated in DU145 cells and mAR activation was unable to further alter the short-term phosphorylation levels of those kinases [8], while long term activation induced significant de-phosphorylation [9].


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

9. Papadopoulou N, Charalampopoulos I, Anagnostopoulou V, Konstantinidis G, Föller M, Gravanis A, Alevizopoulos K, Lang F, Stournaras C: Membrane androgen receptor activation triggers downregulation 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 2008, 7:88.

31. Dambaki C, Kogia C, Kampa M, Darivianaki K, Nomikos M, Anezinis P, Theodoropoulos PA, Castanas E, Stathopoulos EN: Membrane testosterone binding sites in prostate carcinoma as a potential new marker and therapeutic target: study in paraffin tissue sections. BMC Cancer 2005, 5:148

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