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

Li, L.; Ittmann, Michael; Ayala, Gustavo; Tsai, Ming Jer; Amato, Robert J.; Wheeler, Thomas M.; Miles, Brian J.; Kadmon, Dov; Thompson, Timothy C.

doi:10.1038/sj.pcan.4500776

Cited by 110 publications

(115 citation statements)

References 113 publications

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“…5 Akt has three domains with specific functions. The N-terminal domain is a pleckstrin homology (PH) domain, which can bind phosphoinositides (PI) in the cellular membrane.…”

Section: Akt Form and Functionmentioning

confidence: 99%

“…Therefore, PTEN is probably the more important inhibitor. 5 Other recently discovered phosphatases include C-terminal modulator protein and PH domain leucine-rich repeat protein phosphatase, both of which may be significant in Akt regulation. 8 Direct deactivation of Akt is also possible.…”

Section: Upstream Inhibitorsmentioning

confidence: 99%

“…The complex activity of these regulatory proteins is controlled through cell wall constituents including palmitate, integrin and caveolin. 5 Heat shock protein 90 may oppose the actions of these phosphatases, thereby promoting Akt activity. 9 …”

Section: Upstream Inhibitorsmentioning

confidence: 99%

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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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“…5 Akt has three domains with specific functions. The N-terminal domain is a pleckstrin homology (PH) domain, which can bind phosphoinositides (PI) in the cellular membrane.…”

Section: Akt Form and Functionmentioning

confidence: 99%

Section: Upstream Inhibitorsmentioning

confidence: 99%

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Inhibition of Akt pathways in the treatment of prostate cancer

Nelson

Evans

Mack

et al. 2007

Prostate Cancer Prostatic Dis

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“…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.…”

Section: Clinical and Pathologic Characteristicsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Erdamar

Dai

et al. 2007

Human Pathology

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SummaryIn vitro studies suggest that the proapoptotic function of forkhead protein FKHR is probably inactivated by means of phosphorylation through the protein kinase B pathway. However, the clinical significance of FKHR in prostate cancer remains unclear. Six hundred forty radical prostatectomies were used for building tissue microarrays. Slides were stained with antibodies against FKHR and phosphorylated FKHR (p-FKHR). Correlations with clinicopathologic parameters were analyzed by Spearman rank test. Cox regression test and Kaplan-Meier test were used to determine the probability of disease recurrence, which is defined as a serum prostate-specific antigen (PSA) level greater than 0.4 ng/mL after radical prostatectomy. Nuclear FKHR level was higher in normal prostate than in benign prostatic hyperplasia and prostate cancer (P = .0000). Nuclear expression of FKHR was correlated with preoperative PSA level (ρ = 0.108, P = .029), extracapsular extension (ρ = 0.137, P = .005), and seminal vesicle invasion (ρ = 0.101, P = .039). FKHR expression was not a significant indicator of biochemical failure by either univariate or multivariate analysis. Nuclear p-FKHR expression correlated with patients' age (ρ = 0.179, P = .0003), Gleason score (ρ = 0.130, P = .0083), extracapsular extension (ρ = 0.227, P = .0000), clinical stage (Union Internationale Contre le Cancer system) (ρ = 0.166, P = .0007), and lymph node status (ρ = 0.101, P = .0401). Cytoplasmic p-FKHR correlated with patients' age (ρ = 0.146, P = .0030) and clinical stage (ρ = 0.117, P = .0180). Cytoplasmic p-FKHR was a significant indicator of biochemical recurrence (P = .0164; hazard ratio, 1.114-2.929). Nuclear p-FKHR strongly correlated with phosphorylated protein kinase B (ρ = 0.368, P = .0000), androgen receptor (ρ = 0.385, P = .0000), and Skp-2 (ρ = 0.170, P = .0036). Our data suggest that the proapoptotic role of FKHR is probably regulated by several signaling pathways in prostate cancer.

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TRPM4 regulates Akt/GSK3‐β activity and enhances β‐catenin signaling and cell proliferation in prostate cancer cells

Sagredo

Cappelli

et al. 2017

Molecular Oncology

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Increased expression of the TRPM4 channel has been reported to be associated with the progression of prostate cancer. However, the molecular mechanism underlying its effect remains unknown. This work found that decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells. This effect was associated with a decrease in total β‐catenin protein levels and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional activity. Moreover, TRPM4 silencing increases the Ser33/Ser37/Thr41 β‐catenin phosphorylated population and reduces the phosphorylation of GSK‐3β at Ser9, suggesting an increase in β‐catenin degradation as the underlying mechanism. Conversely, TRPM4 overexpression in LNCaP cells increases the Ser9 inhibitory phosphorylation of GSK‐3β and the total levels of β‐catenin and its nonphosphorylated form. Finally, PC3 cells with reduced levels of TRPM4 showed a decrease in basal and stimulated phosphoactivation of Akt1, which is likely responsible for the decrease in GSK‐3β activity in these cells. Our results also suggest that the effect of TRPM4 on Akt1 is probably mediated by an alteration in the calcium/calmodulin‐EGFR axis, linking TRPM4 activity with the observed effects in β‐catenin‐related signaling pathways. These results suggest a role for TRPM4 channels in β‐catenin oncogene signaling and underlying mechanisms, highlighting this ion channel as a new potential target for future therapies in prostate cancer.

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

Cited by 110 publications

References 113 publications

Inhibition of Akt pathways in the treatment of prostate cancer

Inhibition of Akt pathways in the treatment of prostate cancer

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

TRPM4 regulates Akt/GSK3‐β activity and enhances β‐catenin signaling and cell proliferation in prostate cancer cells

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