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.
"The interplay between oncogenic signal transduction pathways and their downstream mediators has been extensively characterized over the past two decades. These signaling events are transmitted by protein-protein interactions that are frequently regulated by phosphorylation events
. PI3K/Akt signaling is a major signal transduction cascade involved in the regulation of a number of cellular processes including cellular proliferation, survival, and metabolism. "
[Show abstract][Hide abstract] ABSTRACT: There is extensive evidence for the role of aberrant cell survival signaling mechanisms in cancer progression and metastasis. Akt is a major component of cell survival-signaling mechanisms in several types of cancer. It has been shown that activated Akt stabilizes XIAP by S87 phosphorylation leading to survivin/XIAP complex formation, caspase inhibition and cytoprotection of cancer cells. We have reported that TGFbeta/PKA/PP2A-mediated tumor suppressor signaling regulates Akt phosphorylation in association with the dissociation of survivin/XIAP complexes leading to inhibition of stress-dependent induction of cell survival.
IGF1R-dependent colon cancer cells (GEO and CBS) were used for the study. Effects on cell proliferation and cell death were determined in the presence of MK-2206. Xenograft studies were performed to determine the effect of MK-2206 on tumor volume. The effect on various cell death markers such as XIAP, survivin, AIF, Ezrin, pEzrin was determined by western blot analysis. Graph pad 5.0 was used for statistical analysis. P < 0.05 was considered significant.
We characterized the mechanisms by which a novel Akt kinase inhibitor MK-2206 induced cell death in IGF1R-dependent colorectal cancer (CRC) cells with upregulated PI3K/Akt signaling in response to IGF1R activation. MK-2206 treatment generated a significant reduction in tumor growth in vivo and promoted cell death through two mechanisms. This is the first report demonstrating that Akt inactivation by MK-2206 leads to induction of and mitochondria-to-nuclear localization of the Apoptosis Inducing Factor (AIF), which is involved in caspase-independent cell death. We also observed that exposure to MK-2206 dephosphorylated Ezrin at the T567 site leading to the disruption of Akt-pEzrin-XIAP cell survival signaling. Ezrin phosphorylation at this site has been associated with malignant progression in solid tumors.
The identification of these 2 novel mechanisms leading to induction of cell death indicates MK-2206 might be a potential clinical candidate for therapeutic targeting of the subset of IGF1R-dependent cancers in CRC.
BMC Cancer 03/2014; 14(1):145. DOI:10.1186/1471-2407-14-145 · 3.36 Impact Factor
"In the canonical Akt pathway, ligand-bound receptor tyrosine kinases stimulate Phosphatidylinositol 3-kinase (PI3K) to convert phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3)20. Akt binds to PIP3 at the plasma membrane and undergoes post-translational modifications, such as activating Serine 473 phosphorylation2021. Activated Akt then phosphorylates downstream targets to regulate cell behaviors including proliferation and programmed cell death; hyperactivation of this pathway is thus a frequent cause of tumor growth2122. "
[Show abstract][Hide abstract] ABSTRACT: Developing recommendations for prostate cancer prevention requires identification of modifiable risk factors. Maternal exposure to high-fat diet (HFD) initiates a broad array of second-generation adult disorders in murine models and humans. Here, we investigate whether maternal HFD in mice affects incidence of prostate hyperplasia in offspring. Using three independent assays, we demonstrate that maternal HFD is sufficient to initiate prostate hyperproliferation in adult male offspring. HFD-exposed prostate tissues do not increase in size, but instead concomitantly up-regulate apoptosis. Maternal HFD-induced phenotypes are focally present in young adult subjects and greatly exacerbated in aged subjects. HFD-exposed prostate tissues additionally exhibit increased levels of activated Akt and deactivated Pten. Taken together, we conclude that maternal HFD diet is a candidate modifiable risk factor for prostate cancer initiation in later life.
"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). "
[Show abstract][Hide abstract] 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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