Increase of AKT/PKB expression correlates with gleason pattern in human prostate cancer

Abstract

Key words: AKT/protein kinase B; prostate; adenocarcinoma; tumor grade; immunohistochemistryProstate cancer (prostatic adenocarcinoma) is one of the most frequent malignancies and the second-leading cause of cancer mortality in males in Western countries including Germany. [1][2][3] Although prostate cancer is often an indolent disease, 25-30% of the tumors behave aggressively 2 resulting in poor prognosis and eventually in the death of the patients. The present stage of knowledge often does not permit a decision which tumor, when diagnosed, will proceed to an aggressive cancer. There is an urgent need to better understand the biology and biochemistry of prostate cancer to establish new prognostic markers and detect cellular functions suitable for therapeutic interference.AKT/protein kinase B (AKT/PKB or AKT) is a central signaling serine/threonine kinase that has been implicated in the genesis or progression of numerous human tumors, because it regulates many of the key effector molecules involved in apoptosis, anoikis and cell cycle progression. 4,5 Activation of the AKT pathway suppresses apoptotic response, undermines cell cycle control and selectively enhances the production of key growth and survival factors. 4,6 -8 Such alterations have been implicated with the progression of prostate cancer. 9 To date, 3 isoforms of AKT have been identified in humans, AKT1, AKT2 and AKT3. RT-PCR analysis of AKT isoforms revealed expression of AKT1 and AKT2 mRNA only in normal prostate and in prostate tumors unequivocally. 5 Although overexpression of AKT protein has been described in a number of human carcinomas, 12-15 a detailed analysis of the expression of AKT protein in human prostatic tissues and in prostate tumors of different stages of progression has not been carried out so far. We were interested in whether total AKT protein expression is altered in prostate cancer, and if so, whether there is a correlation in expression with tumor grade and with clinicopathological parameters. We investigated AKT expression in benign and malignant prostate tissues by immunohistochemistry, and examined the correlation between AKT expression and the Gleason pattern of the specimen investigated as well as the Gleason score of the tumors. Furthermore, we investigated the association between the intensity of AKT expression and preoperative PSA (prostate specific antigen) serum levels. MATERIAL AND METHODS TissueProstate tissue specimens were obtained with consent from 56 patients who underwent radical prostatectomy for prostate cancer during the period from 1998 through 2001 at the University Hospital Mannheim, Heidelberg University, Germany. The mean patient age was 63.3 Ϯ 4.8 years, with an age range of 52-79 years. The patients did not receive hormonal therapy before prostatectomy and were not diagnosed for metastatic cancer. Preoperative serum levels of PSA ranged from 1-42.6 ng/ml with a mean of 9.6 ng/ml. Prostatic index was not available.Tissues were fixed in buffered 10% paraformaldehyde, dehydrated and embedded in Paraplas...

PI3K signaling pathway is activated by PIK3CA mRNA overexpression and copy gain in prostate tumors, but PIK3CA, BRAF, KRAS and AKT1 mutations are infrequent events

“…Some authors have shown that AKT is upregulated in prostate cancer compared with benign prostatic tissue (BPT), prostatic intraepithelial neoplasia (PIN) and primary tumors graded 2-5 according to Gleason. 33,34 Interestingly, no change in the degree of AKT expression was detected in studies in which tumors had Gleason scores ranging from 6 to 10. 35,36 On the other hand, the staining intensity for pAKT has been reported to be significantly greater in prostate tumors with high Gleason grade (Gleason 8-10).…”

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

“…80,85 Elevated Akt expression and kinase activities are associated with a hormone-resistant phenotype and correlates with a poor prognosis in human prostate cancer and breast cancer. 78,79,85,86 Upstream of Akt, amplification of PI3-K has been reported for prostate, 79 ovarian, 87,88 colon, 88 and breast cancer. 85 Several protein-tyrosine kinases (PTKs), which act upstream of the PI3-K and are important regulators of the PI3-K-Akt pathway, have been found overexpressed in various cancers because of activating mutations or other genetic alterations.…”

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

“…There are three members of the Akt family, Akt1, -2 and -3, and evidence suggests that the three isoforms of Akt have different roles in the development of hormone-resistant breast cancer either via interactions with the oestrogen receptor or via proteins involved in proliferation and apoptosis, for example, mTOR and BAD (Kirkegaard et al, 2005). Akt may play a similar role in the development of HRPC (Liao et al, 2003). Cell line studies demonstrate that low passage LNCaP cells (hormone-sensitive prostate cancer cells) have low basal Akt activity, possibly due to early-stage prostate cancer relying on hormones for growth and survival.…”

“…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).…”