AKT regulates androgen receptor-dependent growth and PSA expression in prostate cancer.
Recurrent prostate cancer (PC) is usually treated with androgen deprivation therapy, which, despite initial success, eventually fails due to the development of androgen-independent PC. Androgen deprivation stimulates a significant increase in the phosphorylation (activation) of Akt, a serine/threonine kinase, which regulates cell growth and survival. Hence, we asked whether the increase in Akt phosphorylation contributes to the development of androgen independence. Akt regulates transcriptional activity of the androgen receptor (AR), and our data show that Akt-stimulated AR transcriptional activity is dependent on androgen-binding to the AR. PC proliferation has both androgen-sensitive and insensitive components. The androgen sensitive component is Akt-dependent, while the androgen-insensitive is not. However, Akt-induced cell survival is largely AR independent, suggesting that the cell stimulates Akt phosphorylation when subjected to androgen deprivation as an alternate pathway to maintain survival.
Mikhailova
Margarita
M
Research Services, VA Northern California HCS, Mather, CA, USA.
Wang
Yu
Y
Bedolla
Roble
R
Lu
Xiao-Hua
XH
Kreisberg
Jeffrey I
JI
Ghosh
Paramita M
PM
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D014105:Tosyl Compounds / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen