High Levels of Phosphorylated Form of Akt-1 in Prostate Cancer and Non-Neoplastic Prostate Tissues Are Strong Predictors of Biochemical Recurrence

Abstract

Akt is a serine-threonine-kinase that phosphorylates proteins in several pathways regulating aspects of metabolism, apoptosis, and proliferation. Akt signaling promotes proliferation and increased cell survival and is thought to play an important role in prostate cancer progression. Tissue microarrays (640 patients) with triplicate cores of nonneoplastic prostate, BPH, and index tumor were immunostained with antibody to Phospho-Akt (Ser473), digitized, and quantified. The expression index (Intensity*Percentage) was used for statistical analysis. P-Akt-1 staining was found in both the non-neoplastic and cancer tissues, predominantly in cytoplasmic locations. High level P-Akt-1 is expressed almost exclusively in cancer. By Kaplan-Meier actuarial model, high expression of P-Akt-1 in prostate cancer was predictive of a higher probability of recurrence on univariate and multivariate analysis. Akt-1 expression was an independent prognostic indicator of biochemical recurrence-free survival when Gleason 6 and 7 patients were analyzed separately. Surprisingly, a high level of P-Akt-1 expression in non-neoplastic tissues is also an independent predictor of biochemical recurrence. This suggests that some patients might have an inherent predisposition to express a high level of P-Akt-1 and, therefore, to have an adverse prognosis. We conclude that P-Akt-1 is most likely involved in the progression of prostate cancer and is an excellent biomarker for biochemical recurrence.

Phosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients

“…Work using human prostate tissue confirms that pAkt 473 is expressed in PIN and invasive prostate cancer, and staining intensity positively correlated with PSA levels and Gleason grades (Ghosh et al, 2003;Altomare and Testa, 2005;Majumder and Sellers, 2005). In addition, a large study of 640 radical prostatectomy specimens demonstrated that high levels of pAkt was predictive of biochemical recurrence (Ayala et al, 2003). Although in our current cohort we did not observe a significant association with pAkt 473 and biochemical recurrence (pAkt 473 ; P ¼ 0.151, results not shown), the Kaplan -Meier curves did separate and the difference in the median time to biochemical recurrence in the two groups was 1.8 year compared to 2.4 years, suggesting that significance might have been meet if a larger cohort had been used.…”

“…Prostate tumours are reported to have significantly higher Akt expression than BPH (Liao et al, 2003), and only 10% of well-differentiated prostate tumours strongly express pAkt compared to 92% of poorly differentiated tumours (Malik et al, 2002;Ayala et al, 2003;Ghosh et al, 2003). Akt1 and Akt2 expression in hormone-sensitive tumours have been associated with shorter time to biochemical relapse; however, no association was reported with the activated forms or with survival (Le Page et al, 2006).…”

Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer

“…Preoperative prostate-specific antigen (pre-PSA) level ranged from 0.3 to 97.5 ng/mL (mean, 10.36 ng/mL), with 30% of patients having a pre-PSA level greater than 10.36 ng/mL. Lower Gleason score (GS) (3)(4)(5)(6) was present in 33% patients, whereas 67% had a higher GS (7)(8)(9)(10). Biochemical recurrence occurred in 15.5% of patients, whereas 5.6% had lymph node (LN) metastases.…”

“…This could explain why PCa can respond to initial androgen withdrawal, but many patients with PCa end up with recurrence and androgen independence, leading to accelerated disease progression and death [2,3]. A number of regulatory pathways such as androgen receptor (AR) signaling pathway [4,5], mitogen-activated protein kinase signaling pathway [6], and Akt/PKB (protein kinase B) signaling pathway [7,8] may play critical roles in prosurvival/proliferation in PCa.…”

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

“…Using tissue microarray technology in a large cohort of patients, we have identified that a high level of P-Akt in prostate cancer was predictive of a higher probability of recurrence on univariate and multivariate analysis with hazard ratios considered high on semiquantitative analysis. 117 Since most patients fall within the Gleason 6 and 7 categories, and because of the known limitations of Gleason scoring, we tested P-Akt for its predictive capacity within the subgroup. We found that P-Akt level is also an independent prognostic indicator of survival when Gleason 6 and 7 patients were analyzed separately.…”