Akt in Prostate Cancer: Possible Role in Androgen-Independence

Ghosh, Paramita M.; Malik, Shazli N.; Bedolla, Roble; Kreisberg, Jeffrey I.

doi:10.2174/1389200033489226

Cited by 77 publications

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“…Cell line work demonstrates that Akt activity increases during androgen ablation to stimulate cell growth and survival when androgen reliance is weaker, and therefore promote development of HRPC (Gao et al, 2003;Ghosh et al, 2003;Lin et al, 2003). 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).…”

Section: Protein Expression Patternsmentioning

confidence: 90%

“…However, during hormone ablation or antihormone treatment, LNCaP cells undergo growth arrest and apoptosis, and Akt activity is upregulated (more than 20-fold higher), resulting in stimulation of cell growth, compensating for the effects of androgen withdrawal (Gao et al, 2003). Data from these experiments suggest that Akt signals for cell growth and survival at low levels of androgen, and therefore may promote development of HRPC (Ghosh et al, 2003;Lin et al, 2003). This is supported by a report that demonstrates that upregulation of the PI3K cascade allows cells to grow in the presence of antiandrogens and contributes to failure of endocrine therapy (Murillo et al, 2001).…”

mentioning

confidence: 89%

“…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).…”

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confidence: 99%

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

et al. 2008

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Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (P ¼ 0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (P ¼ 0.014), and an increase in expression of pAkt 473 and pAR 210 were associated with decreased disease-specific survival (P ¼ 0.0019 and 0.0015, respectively). Protein expression of pAkt 473 and pAR 210 also strongly correlated (Po0.001, c.c. ¼ 0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target.

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Section: Protein Expression Patternsmentioning

confidence: 90%

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confidence: 89%

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confidence: 99%

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

et al. 2008

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“…The PI3K/Akt pathway plays an important role in regulating prostate cancer cell proliferation (33)(34)(35)(36), and the Notch signaling pathway has been shown to activate Akt (37,38). It is, therefore, reasonable to examine whether the activity of Akt can be enhanced by Jagged1 together with AR, and whether some relationships exist among them to enhance the cyclin B1 expression level as determined in Fig.…”

Section: Jagged1 Together With Ar Enhances the Expression Level Of Cymentioning

confidence: 99%

Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation

Yan¹,

Guan

Huang³

et al. 2014

Molecular Cancer Research

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The Jagged1, a Notch signaling pathway ligand, had been shown to have a positive correlation with prostate cancer development. Our study for Jagged1 expression in 218 prostate cancer tissue samples also supports this conclusion. However, the detailed molecular mechanism of Jagged1 in promoting the progression of prostate cancer is still unclear. Through cell proliferation examination, androgen receptor (AR) was found to promote the oncogenic function of Jagged1 to enhance the cell proliferation rate by comparing four prostate cancer cell lines, LNCaP, LAPC4, DU145, and PC3, which was further validated through analyzing the survival of 118 patients treated with androgen-deprivation therapy (ADT) with different expression levels of Jagged1 and AR. More importantly, our data showed that Jagged1 combined with AR could increase the phosphorylation level of Akt and, in turn, phosphorylated Akt plays an important role in regulating the expression level of cyclin B1 by interacting with AR and increasing the transcriptional activity of AR. These data indicate that prostate cancer progression regulated by Jagged1 can be dramatically enhanced by combining with AR through promoting Akt activity.

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“…Previous work suggested that rather than inhibit PI3K, the 3-deoxy-PI compounds inhibit the serine/ threonine protein kinase Akt by binding tightly to its PH domain, which normally binds PI(3,4) P 2 or PI (3,4,5), and trapping it in the cytoplasm, thereby preventing phosphorylation by effector kinases. 7 The spectrum of changes in cells caused by these 3-deoxy-PI molecules differs from other widely studied cell growth inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

et al. 2008

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D-3-Deoxy-phosphatidylinositol derivatives have cytotoxic activity against various human cancer cell lines. These phosphatidylinositols have a potentially wide array of targets in the phosphatidylinositol-3-kinase (PI3K)/Akt signaling network. To explore the specificity of these types of molecules, we have synthesized D-3-deoxy-dioctanoylphosphatidylinositol (D-3-deoxydiC 8 PI), D-3,5-dideoxy-diC 8 PI and D-3-deoxy-dioctanoylphosphatidylinositol-5-phosphate and their enantiomers, characterized their aggregate formation by novel high resolution field cycling 31 P NMR, and examined their susceptibility to phospholipase C (PLC) and their effects on the catalytic activity of PI3K and PTEN against diC 8 PI and dioctanoylphosphatidylinositol-3-phosphate substrates, respectively, as well as their ability to induce the death of the U937 human leukemic monocyte lymphoma cells. Of these molecules, only D-3-deoxy-diC 8 PI was able to promote cell death; it did so with an IC 50 of 40 μM, well below the CMC of 0.4 mM. Under these conditions, there was little inhibition of PI3K or PTEN observed in assays of recombinant enzymes (although the complete series of deoxy-PI compounds did provide insights into ligand binding by PTEN). The D-3-deoxydiC 8 PI was a poor substrate and not an inhibitor of the PLC enzymes. The in vivo results are consistent with the current thought that the PI analogue acts on Akt1 since the transcription initiation factor eIF4e, which is a downstream signaling target of the PI3K/Akt pathway, exhibited reduced phosphorylation on Ser209. Phosphorylation of Akt1 on Ser473, but not Thr308, was reduced. Since the potent cytotoxicity for U937 cells is completely lost with the L-3-deoxy-diC 8 PI as well as with modification of the hydroxyl group at the inositol C5 (either replacing the -OH with a hydrogen or phosphorylating it) in D-3-deoxy-diC 8 PI, both chirality of the phosphoinositol moiety and the hydroxyl group at C5 are major determinants of 3-deoxy-PI binding to its target in cells.

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Akt in Prostate Cancer: Possible Role in Androgen-Independence

Cited by 77 publications

References 0 publications

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

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

Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

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