Phospho-Akt Immunoreactivity in Prostate Cancer: Relationship to Disease Severity and Outcome, Ki67 and Phosphorylated EGFR Expression

Abstract

BackgroundIn the present study, we have investigated the prognostic usefulness of phosphorylated Akt immunoreactivity (pAkt-IR) in prostate cancer using a well-characterised tissue microarray from men who had undergone transurethral resection due to lower urinary tract symptoms.Methodology/Principal FindingspAkt-IR in prostate epithelial and tumour cells was assessed using a monoclonal anti-pAkt (Ser473) antibody. Immunoreactive intensity was determined for 282 (tumour) and 240 (non-mlignant tissue) cases. Tumour pAkt-IR scores correlated with Gleason score, tumour Ki67-IR (a marker of cell proliferation) and tumour phosphorylated epidermal growth factor receptor (pEGFR)-IR. For cases followed with expectancy, a high tumour pAkt-IR was associated with a poor disease-specific survival, and the prognostic information provided by this biomarker was additive to that provided by either (but not both) tumour pEFGR-IR or Ki67-IR. Upon division of the cases with respect to their Gleason scores, the prognostic value of pAkt-IR was seen for patients with Gleason score 8–10, but not for patients with Gleason score 6–7.Conclusions/SignificanceTumour pAkt-IR is associated with both disease severity and disease-specific survival. However, its clinical use as a biomarker is limited, since it does not provide prognostic information in patients with Gleason scores 6–7.

Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1

“…Phosphorylation of Thr308 on Akt is activated by PDK1 [81], while the phosphorylation of serine 473 on Akt is activated by mTOR kinase, its associated protein rector, and SIN1/MIP1 [82, 83]. Akt phosphorylation level correlates with higher Gleason score [84, 85]. CAPE treatment caused mild but dose-dependent repression of Akt1, Akt2, as well as phosphorylation of Akt and PDK1 (Figure 7).…”

Improving chemoradiation efficacy by PI3-K/AKT inhibition

“…AKT phosphorylated at Ser473 or Thr308. Moreover, expression of activated AKT has been shown to be associated with a worse outcome in a wide variety of cancers, including cancers of the lung [20], head and neck [21], breast [22,23], brain [24], prostate [25,26], and pancreas [27,28]. However, some studies have reported opposite correlations, whereby high levels of phosphorylated AKT were correlated with a better outcome [29,30].…”

Suppression of interactions between prostate tumor cell‐surface integrin and endothelial ICAM‐1 by simvastatin inhibits micrometastasis

“…Simvastatin also induced apoptosis in prostate cancer cells via simultaneous modulation of intrinsic cell survival and extrinsic apoptotic pathways (Goc et al, 2012b). Simvastatin-induced effects on prostate cancer cells were mainly mediated through the inhibition of Akt, a serine-threonine kinase that has been implicated to be essential for prostate cancer progression and metastasis (Hammarsten et al, 2012, Goc et al, 2011, Goc et al, 2012d). Our studies have also demonstrated the pivotal role of Akt in mediating prostate cancer micrometastasis via activation of integrin α v β 3 (Goc et al, 2012d), which have been reported to be elevated in prostate cancer cells (McCabe et al, 2007).…”