Cellular Interactions of The Phosphorylated Form of AKT in Prostate Cancer

• Published in: Human pathology 2017-05, Vol.63, p.98-109
• Main Authors: Hammerich, Kai H., MD, PhD, Frolov, Anna, Li, Rile, MD, Ittmann, Michael, MD, PhD, Ayala, Gustavo E., MD
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Apoptosis; Biomarkers, Tumor - analysis; Biopsy; Cancer pathway regulation; Cancer therapies; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27 - analysis; Cyclin-dependent kinases; Forkhead Box Protein O1 - analysis; Glycogen Synthase Kinases - analysis; Humans; Immunohistochemistry; Kinases; Male; Metastasis; Middle Aged; Neoplasm Invasiveness; NF-kappa B - analysis; Pathology; Phosphorylation; Prognosis; Prostate cancer; Prostate cancer–related death; Prostate carcinoma; Prostatectomy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Prostatic Neoplasms - surgery; Proteins; Proto-Oncogene Proteins c-akt - analysis; Signal Transduction; Surgeons; Tissue Array Analysis; Transcription factors; Tumor marker; Tumors
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2017.02.014

Phospho-Akt (P-Akt1) promotes proliferation and increased survival in vitro and plays an important role in prostate cancer (PCa) progression as well as the prediction of the probability of recurrence. In this study, the goal was to demonstrate the involvement and impact of P-Akt1 on cellular interactions, biomechanisms and pathways in PCa. Tissue microarrays from 640 PCa patients were immunostained with various antibodies. Ki67 was used to measure proliferation index and Tunnel for apoptotic index. Increased expression of P-Akt1 was associated with an increased proliferation, but inversely correlated with apoptotic index. Higher levels of P-Akt1 are associated with both higher levels of cytoplasmic p27 and higher levels of nuclear p27, suggesting an involvement in both cytoplasmic entrapment and phosphorylation of p27. P-Akt1 expression significantly correlated with nuclear and cytoplasmic staining of FHKR and GSK. The strongest correlations were found with the -P forms of both, suggesting enzyme kinetics in the latter. Here, phosphorylation is the principal method of FHKR and GSK inactivation. P-Akt1 correlated with NFkB, suggesting a role in the inhibition through phosphorylation of NFkB. The results of the current study are unique due to the scope of the markers and the size of the population used. In vitro and in vivo derived information of P-Akt1 and its downstream effectors demonstrate significant involvement in PCa. Our data suggests that PCa uses multiple mechanisms to regulate this pathway and substantiates the concept of redundancy in cancer pathway regulation. Consequently, new hypothesis driven studies can be derived from this information.