Without a doubt, proteasome inhibition with MG132 could partially rescue AR levels inside the presence of Akt i. Phosphorylation dependent degradation of AR has been reported in response to overexpression of cAkt and resulted in phosphorylation dependent AR degradation. Whereas we observed ligand dependent phosphorylation of AR S213 in human prostate tissue and LAPC4 cells, we didn’t observe this in LNCaP cells. In actual fact, whenever we previously overexpressed the LNCaP AR T877A mutant in 293 cells, we observed robust phosphorylation of S213 in wild form AR, but considerably diminished phosphorylation in the mutant. On the other hand, we have not ruled out the likelihood that S213 is constitutively phosphorylated at reduced ranges in LNCaP cells. Regulation of AR from the LNCaP AI subline seems for being independent of Akt. Interestingly, the androgen independent sublines of LNCaP responded differently to Akt inhibition. These cell lines have differing traits that may affect androgen independent development.
Silencing with the cyclin dependent kinase inhibitor p21WAF1 contributes to the androgen independent phenotype of LNCaP AI cells, whereas M phase cell cycle genes this kind of as UBE2C are upregulated selelck kinase inhibitor in LNCaP abl cells. Also, other authors have presented proof of gross differences in AR protein and mRNA regulation in androgen dependent versus independent cells, the latter expressing even more secure AR protein and mRNA. By way of example, pulse chase experiments display that AR protein is two4 occasions even more steady in cells derived from recurring prostate tumors than in LNCaP cells. There are actually also variations in regulation of AR mRNA in androgen dependent versus independent cells: AR transcription is decreased in response to cytokines this kind of as TNF in LNCaP cells but not in androgen independent cells. Conventional anti androgen solutions inhibit the exercise of AR but activation of AR by way of other signaling molecules such as Akt might possibly nonetheless cause illness progression. A number of studies gif alt=”selleckchem kinase inhibitor”> have proven a correlation amongst phosphorylated Akt and prostate cancer progression and recurrence, building Akt an desirable therapeutic target. Regrettably, our acquiring that AR protein amounts will not be decreased in all androgen independent prostate cancer cells examined suggests that the AR pathway will be thoroughly intact even within the presence of Akt inhibitors in some late stage prostate cancers. That is supported by research showing that phase II clinical trials of androgen independent or biochemically recurrent prostate cancer sufferers using the Akt inhibitor perifosine did not significantly improve clinical outcomes. So, a single might possibly speculate that the window of possibility to the clinical utilization of Akt inhibitors to treat prostate cancer may be limited and that these agents may possibly be handy to stop progression of androgen dependent illness to your anti androgen resistant disease stage.