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Current overview of the role of Akt in cancer studies via applied immunohistochemistry

Genzyme Genetics, New York, NY 10019, USA.
Annals of Diagnostic Pathology (Impact Factor: 1.11). 05/2008; 12(2):153-60. DOI: 10.1016/j.anndiagpath.2007.12.001
Source: PubMed

ABSTRACT The family of AKT kinases, AKT-1, 2, and 3, collectively play a crucial role in key processes, as well as pathologic processes such as oncogenesis. The numerous AKT phosphorylation targets include proteins essential to the regulation of cell cycling, protein translation, suppression of programmed cell death, all of which, upon activation via AKT-mediated phosphorylation, promote tumor growth, survival, and aggressiveness. Activation of the AKT pathway can be immunohistochemically detected with antibodies that specifically react with phosphorylated or nonphosphorylated forms of AKT. The following review summarizes the use of phospho-AKT immunohistochemistry as a potentially valuable tool in cancer prognostication in a wide spectrum of common and uncommon malignancies, including squamous carcinoma of cervix and of head and neck; adenocarcinoma of endometrium, ovarian, breast, prostate, kidney, colon, and pancreas; carcinomas of lung and thyroid; and hematopoietic, soft tissue, and central nervous system neoplasms. To date, the findings overall suggest that the major use of p-AKT immunohistochemical staining lies in prognostication and possibly in individualization of therapy rather than in differential diagnosis.

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    • "FOXO transcription factors (DAF-16 isoforms in Caenorhabditis elegans) are among the inactivated targets, as their phosphorylation by the AKT complex prevents their entry into the nucleus (Tissenbaum and Ruvkun, 1998; Berdichevsky et al., 2006). AKT mutations conferring constitutive activation are observed in many cancers (Shtilbans et al., 2008); mutations in the pten gene, disrupting the PI 3-phosphatase that opposes PI3K, also produce a high PIP 3 /PIP 2 ratio, favoring activated AKT and hence cell proliferation in diverse cancers (Yi et al., 2005). Although direct constitutive activation of PI3K is far less common, the BCR-ABL fusion protein indirectly activates PI3K, thus elevating PIP 3 in chronic myelogenous leukemia (Kharas et al., 2008). "
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    ABSTRACT: The regulation of animal longevity shows remarkable plasticity, in that a variety of genetic lesions are able to extend lifespan by as much as 10-fold. Such studies have implicated several key signaling pathways that must normally limit longevity, since their disruption prolongs life. Little is known, however, about the proximal effectors of aging on which these pathways are presumed to converge, and to date, no pharmacologic agents even approach the life-extending effects of genetic mutation. In the present study, we have sought to define the downstream consequences of age-1 nonsense mutations, which confer 10-fold life extension to the nematode Caenorhabditis elegans - the largest effect documented for any single mutation. Such mutations insert a premature stop codon upstream of the catalytic domain of the AGE-1/p110α subunit of class-I PI3K. As expected, we do not detect class-I PI3K (and based on our sensitivity, it constitutes <14% of wild-type levels), nor do we find any PI3K activity as judged by immunodetection of phosphorylated AKT, which strongly requires PIP3 for activation by upstream kinases, or immunodetection of its product, PIP3. In the latter case, the upper 95%-confidence limit for PIP3 is 1.4% of the wild-type level. We tested a variety of commercially available PI3K inhibitors, as well as three phosphatidylinositol analogs (PIAs) that are most active in inhibiting AKT activation, for effects on longevity and survival of oxidative stress. Of these, GDC-0941, PIA6, and PIA24 (each at 1 or 10 μM) extended lifespan by 7-14%, while PIAs 6, 12, and 24 (at 1 or 10 μM) increased survival time in 5 mM peroxide by 12-52%. These effects may have been conferred by insulinlike signaling, since a reporter regulated by the DAF-16/FOXO transcription factor, SOD-3::GFP, was stimulated by these PIAs in the same rank order (PIA24 > PIA6 > PIA12) as lifespan. A second reporter, PEPCK::GFP, was equally activated (∼40%) by all three.
    Frontiers in Genetics 03/2013; 4:34. DOI:10.3389/fgene.2013.00034
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    • "[24] M. Shimizu, Y. Shirakami, H. Moriwaki, Targeting receptor tyrosine kinases for chemoprevention by green tea catechin, EGCG, Int J Mol Sci 9 (2008) 1034-1049. [25] V. Shtilbans, M. Wu, D.E. Burstein, Current overview of the role of Akt in cancer studies via applied immunohistochemistry, Ann Diagn Pathol 12 (2008) 153-160. "
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    ABSTRACT: Regular consumption of green tea benefits people in prevention from cardiovascular disorders, obesity as well as neurodegenerative diseases. (-)-Epigallocatechin-3-gallate (EGCG) is regarded as the most biologically active catechin in green tea. However, the stability and bioavailability of EGCG are restricted. The purpose of the present study was to investigate whether a pro-drug, a fully acetylated EGCG (pEGCG), could be more effective in neuroprotection in Parkinsonism mimic cellular model. Retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cells were pre-treated with different concentrations of EGCG and pEGCG for 30 min and followed by incubation of 25 microM 6-hydroxydopamine (6-OHDA) for 24h. We found that a broad dosage range of pEGCG (from 0.1 to 10 microM) could significantly reduce lactate dehydrogenase release. Likewise, 10 microM of pEGCG was effective in reducing caspase-3 activity, while EGCG at all concentrations tested in the model failed to attenuate caspase-3 activity induced by 6-OHDA. Furthermore, Western-blot analysis showed that Akt could be one of the specific signaling pathways stimulated by pEGCG in neuroprotection. It was demonstrated that 25 microM of 6-OHDA significantly suppressed the phosphorylation level of Akt. Only pEGCG at 10 microM markedly increased its phosphorylation level compared to 6-OHDA alone. Taken together, as pEGCG has higher stability and bioavailability for further investigation, it could be a potential neuroprotective agent and our current findings may offer certain clues for optimizing its application in future.
    Neuroscience Letters 12/2009; 469(3):360-4. DOI:10.1016/j.neulet.2009.12.028 · 2.06 Impact Factor
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    • "ion to specific membrane receptors , induce the activation of different signalling pathways leading to the regula - tion of transcription factors , thereby coordinating adequate cell response ( i . e . cell growth , death or differentiation ) . Akt is one of the major components of the PI3 - kinase pathway and is com - monly activated in tumours ( Shtilbans et al . , 2008 ) . Akt is a key regulator in survival and plays an important role in the regula - tion of cell fate choices during haematopoietic lineage commitment ( Buitenhuis et al . , 2008 ) . Prevention of cell death is known to be one of the crucial events in myeloid leukemogenesis and affects genetic instability and the acquisition of additiona"
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    ABSTRACT: Defining the impact on health of exposure to a low-dose pesticide mixture via food intake is a topical question since epidemiological studies suggest that this may increase the risk of pathologies and particularly haematopoietic malignancies. Here we investigated on the haematopoietic system of mice, the effect of a mixture of six pesticides frequently ingested through the intake of fruits and vegetables produced in France (alachlor, captan, diazinon, endosulfan, maneb, mancozeb). The mixture was administered repeatedly by gavage to mice for 4 weeks at levels derived from the human Acceptable Daily Intake (ADI) level adapted to the mean weight of mice. Using a NMR-based metabonomic approach, we show that this treatment led to specific gender-linked variations in the level of hepatic metabolites involved in oxidative stress and in the regulation of glucose metabolism, indicating a metabolic signature for this repeated administration. Interestingly, exposure to the low-dose pesticide mixture induced significant changes in the blood cell counts with modifications in the clonogenic and differentiating capacities of haematopoietic progenitors showing abnormalities in the granulocytic and monocytic lineages in female and male mice, respectively. From a molecular point of view, the changes induced by the pesticide treatment correlated with modifications of the PI 3-kinase/Akt signalling pathway, the tyrosine kinase Pyk2 and the c-Myc transcription factor, which are involved in the balance between self-renewal and differentiation of haematopoietic stem cells. Our results point to a significant effect of a very low dose of a mixture of commonly used pesticides on mice metabolism and haematopoietic system with major differences between males and females.
    Toxicology 10/2009; 267(1-3):80-90. DOI:10.1016/j.tox.2009.10.024 · 3.75 Impact Factor
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