AKT In Cancer Research Articles

Characterization of fenugreek and its natural compounds targeting AKT-1 protein in cancer: Pharmacophore, virtual screening, and MD simulation techniques

ObjectiveCancer is the second biggest cause of death in humans. Rapid advancements in clinical bioinformatics and high-throughput proteomics technology are essential tools and methodologies for cancer research. Medicinal plants are considered operative therapeutic agents that are utilized for novel drug discovery and development, using computer-aided drug design (CAAD). The AKT-1 Serine/Threonine Kinase family was chosen as the target protein because it is implicated in the mediation of the cancer process. In this work, phytocompounds that target AKT-1 in cancer were recognized and were used to identify their binding relationship with the nominated receptor. MethodsA dried extraction of Fenugreek (Trigonella foenum-graecum) seeds in solid form was obtained using an evaporation technique and phytochemicals present in it were tested using qualitative tests. Fenugreek and its natural components were evaluated against AKT-1 because chemical agents acquired from natural sources appear to be particularly appealing alternatives to synthetic compounds. Different bioinformatics computational methods were used for protein structural analysis, interactive comparison, alignment, and superposition of AKT-1 protein structures in 3D. By using molecular docking and molecular dynamic (MD) simulation experiments, the binding interaction of the selected compounds with AKT-1 was investigated. ResultsFenugreek seeds yielded by phytochemicals screening and crude extractions of tannins, saponin, steroids, and cardiac glycosides were found to have very high antioxidant activity. After virtual screening hits, the top three phytocompounds (Compound-1 tannins, Compound-2 saponins, and Compound-3 steroids) were selected against AKT-1 on the basis of their strong binding energy (−10.9 to −9.2 Kcal/mol). Compound-1 showed the highest pharmacophore fit score (43.91) among all compounds. In molecular interactions, some crucial residues (Gln-79, Trp-80, Thr-82, Val-270, Tyr-272, Asp-274, and Asp-292) were observed at binding pockets of AKT-1. MD simulations at 100 ns revealed that the ligand was bound to the protein with some major conformational changes in the protein structure. ConclusionsIn-silico studies report new dimensions for novel drug design targeting AKT-1. The three leading hits inhibit the cancer cell's inflammation activity in the AKT-1 pathway. In the future, these three compounds might be tested for the drug discovery of inflammatory disorders.

Virtual Docking Screening and QSAR Studies to Explore PI3K and mTOR Inhibitors Acting on AKT in Cancers

The PI3K / AKT / mTOR pathway is an important regulator of a wide range of cellular processes including survival, proliferation, growth, metabolism, angiogenesis and metastasis. PI3K induces translocation of Ser / Thr Akt kinase, Akt is activated by PDK1 and mTOR2-dependent phosphorylations. Aberrant activation of the PI3K / AKT / mTOR pathway is frequently observed in many human malignancies and the combination of compounds simultaneously targeting different related molecules in the PI3K / AKT / mTOR pathway leads to synergistic activity. To explore the common AKT / mTOR and AKT / PI3K competitor ATP inhibitors we performed a 2D AKT-SAR model to predict the bioactivity of PI3K and mTOR inhibitors on AKT, the interaction of the best inhibitors was evaluated by docking analysis and compared to that of GSK690693 and Ipatasertib. An AKT-SAR model with a correlation coefficient (R2) of 0.85212 and an RMSE of 0.09266 was obtained, which was validated and evaluated by a cross-validation method LOO, the most predicted inhibitors of PI3K and mTOR respectively PIC50 activities between [9.30 - 8.54], and [9.79 - 8.91]. After docking and several comparisons, inhibitors with better predictions showed better affinity and interaction with AKT compared to GSK690693 and Ipatasertib. We therefore found that 8 PI3K inhibitors and 11 mTOR inhibitors met the Lipinski and Veber criteria and could be future drugs.

Akt in cancer: Mediator and more.

Akt is a serine/threonine kinase and it participates in the key role of the PI3K signaling pathway. The Akt can be activated by a wide range of growth signals and the biochemical mechanisms leading to Akt activation are well defined. Once activated, Akt modulates the function of many downstream proteins involved in cellular survival, proliferation, migration, metabolism, and angiogenesis. The Akt is a central node of many signaling pathways and it is frequently deregulated in many types of human cancers. In this review, we provide an overview of Akt function and its role in the hallmarks of human cancer. We also discussed various mechanisms of Akt dysregulation in cancers, including epigenetic modifications like methylation, post-transcriptional non-coding RNAs-mediated regulation, and the overexpression and mutation.

Abstract 4613: SMYD3-mediated lysine methylation is critical for the activation of AKT1 in human cancer

Abstract v-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT1), a serine/threonine-protein kinase also known as protein kinase B Alpha (PKB Alpha), is a key mediator of a signaling pathway that governs various cellular processes regulating cell growth, survival, glucose metabolism, genome stability and neovascularization. It is known that dysregulation of AKT1 activity is one of the critical factors for the development and/or progression of a variety of human cancers. Posttranslational modifications of AKT1, including phosphorylation, ubiquitination and glycosylation, are well-analyzed, and it is known that the phosphorylation status of AKT1 is strongly correlated with its oncogenic activity. However, biological functions of methylation on AKT1 have never been analyzed so far. In the present study, we demonstrated that the protein lysine methyltrasnferase SMYD3 methylates lysine 14 in the PH domain of AKT1, which is known to play a critical role in the regulation of AKT1 activity through binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) or phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), in vitro and in vivo. Lysine 14-substituted AKT1 shows significantly lower levels of phosphorylation at threonine 308, which is the major indicator of AKT1 activity, than wild-type AKT1, and knockdown of SMYD3 as well as treatment with a SMYD3 inhibitor significantly attenuates this phosphorylation in cancer cells. Furthermore, substitution of lysine 14 diminishes the plasma membrane accumulation of AKT1, and cancer cells overexpressing lysine 14-substiuted AKT1 shows lower growth rate than those overexpressing wild-type AKT1. These results imply that SMYD3-mediated methylation of AKT1 at lysine 14 plays a central role in the oncogenic activity of AKT1. Although Phosphatidylinositide 3-kinase (PI3K)-dependent AKT1 phosphorylation by Pyruvate Dehydrogenase Kinase, Isozyme 1 (PDK1) and mTOR Complex 2 (mTORC2) has long been considered to be the primary mechanism accounting for AKT1 activation, these members are not sufficient enough to explain how AKT1 hyperactivation can occur in tumors with normal levels of PI3K/Phosphatase And Tensin Homolog (PTEN) activity. Our findings unveiled the novel mechanism of constitutive hyperphosphorylation on AKT1 in cancer cells, mediated by SMYD3-mediated methylation. The inhibition of this methylation pathway appears to be a promising strategy to develop anti-cancer drugs. Citation Format: Yuichiro Yoshioka, Yusuke Nakamura, Ryuji Hamamoto. SMYD3-mediated lysine methylation is critical for the activation of AKT1 in human cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4613.

AKT in cancer: new molecular insights and advances in drug development.

The phosphatidylinositol-3 kinase (PI3K)-AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K-AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well-characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT.

Emerging therapeutics for targeting Akt in cancer.

The ultimate goal of cancer therapeutic research is to develop effective, targeted therapeutics that exploit the vulnerabilities of cancer cells. The three isoforms of Akt, also known as protein kinase B (PKB), are important mediators of various pathways that transmit mitogenic signals from the cell's exterior to the effector proteins of the cell's interior. Due to Akt\\\\\\\'s importance in cell functions such as growth, proliferation and cell survival, many cancer cells rely on this pathway to aid in their survival. This dependence can lead to chemoresistance and selection of more adapted populations of cancer cells. Thus, it is important to understand the functional significance of isoform specificity and its relation to chemoresistance. In this review, we have summarized recent studies on Akt isoform specific regulation as well as each isoform's role in chemoresistance, emphasizing their potential as targets for cancer therapy. We have also condensed ongoing clinical studies involving various types of Akt inhibitors while highlighting the type of study, rationale and co-therapies involved in identifying Akt isoforms as promising therapeutic targets.

PI3K and AKT: Unfaithful Partners in Cancer.

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway regulates multiple cellular processes. An overactivation of the pathway is frequently present in human malignancies and plays a key role in cancer progression. Hence, its inhibition has become a promising approach in cancer therapy. However, the development of resistances, such as the abrogation of negative feedback mechanisms or the activation of other proliferative signaling pathways, has considerably limited the anticancer efficacy of PI3K/AKT inhibitors. In addition, emerging evidence points out that although AKT is acknowledged as the major downstream effector of PI3K, both PI3K and AKT can operate independently of each other in cancer, revealing another level of complexity in this pathway. Here, we highlight the complex relationship between PI3K and AKT in cancer and further discuss the consequences of this relationship for cancer therapy.

Diverse involvement of isoforms and gene aberrations of Akt in human lung carcinomas.

Emerging evidence confirms a central role of Akt in cancer. To evaluate the relative contribution of deregulated Akt and their clinicopathological significance in lung carcinomas, overexpression, activation of Akt and AKT gene increases were investigated. Immunohistochemical staining for 108 cases revealed overexpression of total Akt, Akt1, Akt2 and Akt3 in 61.1, 47.2, 40.7 and 23.1%, respectively, and phosphorylated Akt in 42.6% of cases. Expression of total Akt, Akt2 and Akt3 were frequently observed in small cell carcinoma, but phosphorylated Akt and Akt1 were more frequently observed in squamous cell carcinoma. FISH analysis to evaluate gene increases of AKT1-3 revealed amplification of AKT1 in 4.2% and AKT1 increase by polysomy of chromosome 14 in 27.3% of cases. For AKT2, amplification was observed in 3.2% and polysomy of chromosome 19 in 26.3% of cases. AKT3 increase was observed in 40.0% of cases only by polysomy of chromosome 1. Although “FISH-positive” AKT1 and AKT2 gene increases (amplification/high-level polysomy) were found exclusively in the cases overexpressing total Akt, Akt1 or Akt2, respectively, AKT3 increase was irrelevant of Akt3 expression. Statistically, expressions of Akt2, p-Akt and cytoplasmic-p-Akt were correlated with lymph node metastasis (P = 0.0479, P = 0.0371 and P = 0.0310, respectively). Although AKT1 and AKT2 gene increase showed positive correlation with, or trend towards a positive correlation with tumor size (P = 0.0430, P = 0.0590, respectively), AKT3 did not. In conclusion, Akt isoforms are differentially involved in the pathological phenotype of lung carcinoma in a diverse manner. Because abnormality of Akt1/AKT1 and Akt2/AKT2 correlated with clinicopathological profiles, Akt1/2-specific targeting may open a novel therapeutic window for the group showing Akt deregulation.

Significance of AKT in gastric cancer(Review).

AKT is a serine/threonine kinase activated downstream of integrin, which is a receptor for various pro-proliferation and bioactive substances as well as the extracellular matrix receptor. The activation of AKT often contributes to tumorigenesis and plays a role in regulating cell motility, which is critical for local invasion and metastasis. In recent years, it has also drawn attention as a target of new molecular-targeted agents. When analyzing the role of AKT in cancer cells, it is important to consider the microenvironment and variations of cancers. In this review, a basic overview of the role of AKT in normal and malignant tissues is provided, along with an in-depth discussion of its role in gastric cancer and its potential as a target for therapy.

Alteration in methylation pattern of oncogene Akt1 promoter region in bladder cancer

The oncogene Akt1 plays a pivotal role in regulating growth factor-associated cell survival. The activity of Akt must be carefully regulated as it has been reported that an increase in Akt signaling is frequently associated with cancer. Phosphorylated Akt, as the constitutively activated form of Akt, has been observed in many kinds of cancer, but the clinical relevance of the (DNA) methylation profile of Akt1 in cancer is not well understood. This study aims to investigate the methylation level of Akt1 in bladder cancer tissues and their clinical significance. Methylation of the oncogene Akt1 transcriptional regulation region (TRR) was detected using bisulfite-specific (BSP) PCR-based sequencing analysis in cases of bladder cancer and the normal tissues, including 15 bladder cancer tissues, and five normal bladder tissues. BSP cloning-based sequencing analysis was also performed in selected cases. Clinicopathological data from the cancer patients were collected and analyzed. Analysis of Akt1 gene TRR methylation showed decreased methylation level in bladder cancer than normal. Methylation level of Akt1 has clinical relevance (P=0.0043 by unpaired student's t test) with bladder cancer. Abnormal methylation of the Akt1 gene may be an early event during urocystic tumorigenesis and should be further evaluated as a tumorigenesis marker for early detection of bladder cancer.

Regulation, Role, and Targeting of Akt in Cancer

The serine-threonine kinase AKT, also known as protein kinase B (PKB), was identified in 1977 as the proto-oncogene of the v-Akt oncogenic murine thymoma virus. Subsequent research has demonstrated that genetic events activating Akt occur in most types of cancer. Activation of Akt promotes many of the processes critical to the malignant phenotype. Thus, Akt is an attractive therapeutic target for cancer. However, its critical role in many physiologic processes suggests that achieving an acceptable therapeutic index with Akt inhibitors may be a challenge. In Journal of Clinical Oncology, Yap et al report the results of, to our knowledge, the first-in-man phase I clinical trial of Akt inhibitor MK-2206. In addition to determining the maximum-tolerated dose of MK-2206, the study included a pharmacodynamic analysis of hair follicles in the majority of patients, and of paired tumor biopsies in a maximum-tolerated dose expansion cohort. The results provide strong evidence that significant inhibition of Akt is feasible in patients. However, limited single-agent antitumor activity was observed. This Understanding the Pathway report will highlight the current understanding of the role and regulation of Akt signaling in cancer and the implications for further development of therapeutic strategies against this critical signaling node. Akt is a member of the AGC family of protein kinases. Akt has three isoforms: Akt1 (also known as PKB ), Akt2 (PKB ), and Akt3 (PKB ). Akt1 and Akt2 are expressed in most tissue types; Akt3 expression is generally restricted to neuronal tissue and the testes. The three isoforms share over 80% homology and are characterized by three conserved functional domains: an amino-terminal pleckstrin homology (PH) domain that regulates intracellular trafficking of the protein, a central catalytic domain, and a carboxy-terminal regulatory domain. Activation of all three Akt isoforms is dependent on phosphatidylinositol 3-kinase (PI3K). PI3K is stimulated by a variety of signals, including growth factor and G protein–coupled receptors on the cell surface. Activation of PI3K results in the generation of 3 phosphorylated phosphatidylinositols in the cell membrane, which recruit Akt and other PH domain–containing proteins to the cell membrane. At the cell membrane, Akt comes into proximity with PDK1, another PH domain–containing serine-threonine kinase, which phosphorylates Akt at the Thr308 residue of its catalytic domain. The activated conformation of Akt is further stabilized by phosphorylation at the Ser473 residue, either by the mammalian target of rapamycin complex 2 in response to growth factor stimulation or by

Targeting Akt in Cancer: Promise, Progress, and Potential Pitfalls

Targeting Akt in Cancer: Promise, Progress, and Potential Pitfalls

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.

Regulation of the activity of p38 mitogen-activated protein kinase by Akt in cancer and adenoviral protein E1A-mediated sensitization to apoptosis.

The adenoviral early region 1A (E1A) protein mediates sensitization to different stimulus-induced apoptosis, such as tumor necrosis factor alpha, UV and gamma irradiation, and different categories of anticancer drugs. However, the molecular mechanisms underlying E1A-mediated sensitization to apoptosis are still not completely defined. Here, we show that E1A-mediated sensitization to apoptosis by the inactivation of a key survival factor Akt and the activation of a pro-apoptotic factor p38. Also, inactivation of Akt by either a specific inhibitor or a genetic knockout of Akt1 results in p38 activation, possibly through the release of the activity of p38 upstream kinases, including ASK1 and MEKK3. In addition, we showed that p38 phosphorylation is downregulated and Akt phosphorylation is upregulated in multiple human tumor tissues, and this correlates with tumor stage in human breast cancer. A deletion mutation of a conserved domain of E1A, which is required for E1A-induced downregulation of Akt activity, disrupts E1A-mediated upregulation of p38 activity and also eliminates E1A-mediated chemosensitization. Thus, activation of p38 and inactivation of Akt may have general implications for tumor suppression and sensitization to apoptosis.