title: Androgen receptor levels are upregulated by Akt in prostate cancer.
abstract: Multiple lines of evidence suggest a functional link between the androgen receptor (AR) and the serine/threonine kinase Akt in the development and progression of prostate cancer. To investigate the impact of Akt activity on AR homeostasis, we treated androgen-dependent LNCaP and LAPC-4 prostate cancer cells with Akt inhibitor. Akt inhibition decreased AR expression, suggesting that Akt activity was required for regulation of AR protein levels. However, while androgen-independent LNCaP-abl cells also showed diminished AR protein levels in response to Akt inhibition, treatment of androgen-independent LNCaP-AI cells failed to alter AR protein levels upon similar treatment, suggesting that AR protein levels in these androgen-independent prostate cells were regulated by mechanisms independent of Akt activation. Regulation of AR, downstream of activated Akt, also was observed in vivo when examining transgenic mice that overexpress constitutively active mutant myristoylated (myr)-Akt1 in the prostate. Transgenic mice expressing activated myr-Akt1 exhibited higher levels of AR mRNA and protein. Expression of activated myr-Akt1 did not alter prostate cell growth and no significant size differences between prostate tissues derived from transgenic animals were observed when comparing transgenic mice with wild-type mice. Still, transgenic mice overexpressing Akt exhibited higher levels of γH2AX and phosphorylated Chk2 in prostate tissue. These changes in markers associated with oncogene-induced senescence confirmed significant altered signaling in the transgenic mouse model. Overall, results presented here suggest that AR levels are regulated by the Akt pathway.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA. susan.logan@nyumc.org
authors.forename: Susan
authors.initials: S
authors.lastname: Ha
authors.forename: Rachel
authors.initials: R
authors.lastname: Ruoff
authors.forename: Nicole
authors.initials: N
authors.lastname: Kahoud
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Franke
authors.forename: Susan K
authors.initials: SK
authors.lastname: Logan
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D002867:Chromones / Q000494:pharmacology; D006657:Histones / Q000096:biosynthesis; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000728:Androgens; D002867:Chromones; D006657:Histones; D009025:Morpholines; D012333:RNA, Messenger; D011944:Receptors, Androgen; C475961:gamma-H2AX protein, mouse; D015741:Metribolone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D064447:Checkpoint Kinase 2; C514862:Akt1 protein, mouse; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt