Phosphorylation of Akt (Ser473) is an Excellent Predictor of Poor Clinical Outcome in Prostate Cancer

Kreisberg, Jeffrey I.; Malik, Shazli N.; Prihoda, Thomas J.; Bedolla, Roble; Troyer, Dean A.; Kreisberg, Suzanne H.; Ghosh, Paramita M.

doi:10.1158/0008-5472.can-04-0272

Cited by 303 publications

(236 citation statements)

References 26 publications

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“…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). [35][36][37] These reports are in concordance with the results of the present study, in which there was statistical correlation between pAKT expression and Gleason score Po0.0001. Finally, we have also found a statistical correlation between pAKT and PIK3CA mRNA overexpression and/or PIK3CA copy gain Po0.0001.…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2011

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The phosphatidylinositol 3-kinase (PI3K)-AKT and RAS-MAPK pathways are deregulated in a wide range of human cancers by gain or loss of function in several of their components. Our purpose has been to identify genetic alterations in members of these pathways in prostate cancer. A total of 102 prostate tumors, 79 from prostate cancer alone (group G1) and 23 from bladder and prostate cancer patients (G2), are the subject of this study. In 20 of these 23, the bladder tumors were also analyzed. PIK3CA, KRAS, BRAF and AKT1 mutations were analyzed by direct sequencing, and BRAF also by pyrosequencing. PIK3CA quantitative mRNA expression and fluorescence in situ hybridization (FISH) gains were tested in 25 and 32 prostate tumors from both groups (G1 and G2), respectively. Immunohistochemistry for pAKT was performed in 55 prostate tumors. Of 25 prostate tumors, 10 (40%) had PIK3CA mRNA overexpression that was statistically associated with Gleason score Z7 (P ¼ 0.018). PIK3CA copy gain was detected in 9 of 32 (28%) prostate tumors. Of 20 bladder tumors, 3 (15%) displayed mutations in PIK3CA, KRAS and AKT1, the corresponding prostate tumors being wt. We also detected a previously not reported PIK3CA polymorphism (IVS9 þ 91) in two prostate tumors. In all, 56% of prostate tumors overexpressed pAKT. There is a statistical association (Po0.0001) of strong pAKT immunostaining with high Gleason score, and with PIK3CA alterations (mRNA overexpression and/or FISH gains). PIK3CA gene is deregulated by mRNA overexpression and DNA gain in B40 and 28% of prostate tumors, respectively. High-grade prostate tumors are associated with PIK3CA mRNA overexpression, but not with FISH status. PIK3CA, BRAF, KRAS and AKT1 mutations are very infrequent events in prostate tumors. However, PI3K signaling pathway is activated by PIK3CA FISH gain and/or mRNA overexpression, leading to an increased pAKT protein expression.

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Section: Discussionsupporting

confidence: 91%

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

et al. 2011

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“…22RV-1, C4-2) harbour highly active PI3K/Akt signalling (Davies et al, 1999;Murillo et al, 2001;Gao et al, 2003). Phosphorylated Akt is also highly expressed in PrCas with high Gleason grade (Malik et al, 2002) and is an excellent predictor of clinical PSA failure (Kreisberg et al, 2004). Chemical inhibitors targeting the catalytic unit of PI3K, such as LY294002 and Wortmanin, induce a potent apoptotic response in most PrCa cell lines including LNCaP, LAPC4 and LAPC9 (Lin et al, 1999).…”

Section: Pi3k/akt and Ar: Critical Regulators Of Progression To Ai Prcamentioning

confidence: 99%

PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer

Mulholland

Dedhar

Wu³

et al. 2006

Oncogene

201

164

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Prostate cancer (PrCa) is characterized by progression from an androgen-dependent phenotype to one that is inevitably androgen independent (AI) and lethal. Recent evidence strongly suggests that the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and androgen receptor (AR) signalling pathways provide prostatic epithelium with the necessary signalling events to escape the apoptotic response associated with androgen withdrawal therapy. Silencing of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and glycogen synthase kinase b (GSK3b) are frequently associated with advanced PrCa systems and likely serve critical roles in promoting AR and PI3K/Akt gain-of-function. That PTEN negatively regulates AR and is sufficient to promote metastatic PrCa in murine models strongly implies its role as a gatekeeper of progressive PrCa. In human PrCa, PTEN loss is correlated with substantial increases in Akt Ser473 and integrin-linked kinase expression, both of which promote Ser 9 phospho-inhibition of GSK3b and inactivation of apoptotic factors. Sufficient evidence also suggests that GSK3b is not only a critical regulator of proproliferative signalling but also a promiscuous one as PI3K/Akt pools of GSK3b are, at least in part, functionally interchangeable with those of the Wnt/b-catenin pathway. Thus, GSK3b may serve not only as a mediator of PI3K/Akt activation but may also regulate the potent transactivation and proproliferative effects that Wnt3a and b-catenin confer upon AR. These data suggest that prostate-specific activation of GSK3b may serve as a viable pharmacological option. Thus, in this review, we emphasize that temporal changes in GSK3b and PTEN expression during progression to AI PrCa are important factors when considering the potential for therapies targeting the oncogenic contributions of PI3K/Akt and AR signalling pathways.

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“…In one report, phosphorylation of Akt was superior to measurements of cellular proliferation and even Gleason grade for predicting biochemical recurrence following radical prostatectomy. 25 Treatments for CaP may also upregulate Akt pathways through activation of cellular stress responses. In CaP specifically, androgen withdrawal may lead to biochemical changes ultimately supporting the emergence of AI disease.…”

Section: Alterations Of Akt Activity In Capmentioning

confidence: 99%

Inhibition of Akt pathways in the treatment of prostate cancer

Nelson

Evans

Mack

et al. 2007

Prostate Cancer Prostatic Dis

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Akt is a serine/threonine kinase mediating multiple intracellular pathways involved in prostate cancer (CaP) biology. Increased understanding of the molecular mechanisms of Akt activation and signaling have led to the development of an increasing number of Akt inhibitors. These biologic agents demonstrate activity against a wide range of cancers in preclinical studies. Clinical studies of Akt inhibition in CaP are in progress, including agents such as celecoxib, perifosine and genistein. How best to integrate Akt inhibitors with standard CaP therapy or select patients most likely to benefit is the subject of ongoing research.

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Phosphorylation of Akt (Ser473) is an Excellent Predictor of Poor Clinical Outcome in Prostate Cancer

Cited by 303 publications

References 26 publications

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

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

PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer

Inhibition of Akt pathways in the treatment of prostate cancer

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