Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer.

Abstract

We previously showed, by immunohistochemistry with phospho-specific antibodies, increased phosphorylation (activation) of Akt (Ser(473)) [phosphorylated Akt (pAkt)] in high-Gleason grade prostate cancer (Malik SN, et al., Clin Cancer Res 2002;8:1168-71). Elevation of pAkt was accompanied by decreased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (Thr(202)/Tyr(204)) [phosphorylated ERK (pERK)], indicative of inactivation. In this report, we determined whether increased pAkt and decreased pERK predicted clinical outcome. Prostate-specific antigen (PSA) failure (detectable and rising PSA) versus PSA non-failure (undetectable PSA 5 years after prostatectomy) was used as a surrogate for clinical outcome. Prostate tumors from cases of PSA failure versus non-failure were stained for pAkt and pERK. A significant increase in mean pAkt staining (P < 0.001) in the PSA failures versus non-failures was seen based on the Wilcoxon signed ranks test [222.18 +/- 33.9 (n = 37) versus 108.79 +/- 104.57 (n = 16)]. Using the best-fitting multiple logistic regression equation, a 100-point increase in pAkt staining resulted in a 160% increase in the odds of being a PSA failure. There was decreased staining for pERK in PSA failures versus non-failures: a 100-point decrease resulted in an 80% increase in the odds of being a PSA failure. Each of these effects assumed the other biomarker was held constant. The area under the receiver-operating characteristic curve for these two biomarkers predicting PSA failure was 0.84, indicating excellent discrimination between PSA failure and non-failure cases. These data indicate that increased pAkt, alone or together with decreased pERK, is an important predictor of probability of PSA failure. However, pERK alone was not a significant predictor of PSA failure.

• Authors: Jeffrey I Kreisberg, Shazli N Malik, Thomas J Prihoda, Roble G Bedolla, Dean A Troyer, Suzanne Kreisberg, Paramita M Ghosh
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 15 Pg. 5232-6 (Aug 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15289328 (Publication Type: Journal Article)

Chemical References

• Proto-Oncogene Proteins
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Prostate-Specific Antigen

Topics

• Adult
• Aged
• Aged, 80 and over
• Disease-Free Survival
• Humans
• Immunoenzyme Techniques
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphorylation
• Predictive Value of Tests
• Prostate-Specific Antigen (metabolism)
• Prostatectomy
• Prostatic Neoplasms (metabolism, pathology)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt