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      Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

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          Abstract

          Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial–mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

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          Most cited references 323

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          Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

          Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
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            CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009.

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              The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.

              The serine/threonine protein kinase encoded by the Akt proto-oncogene is catalytically inactive in serum-starved primary and immortalized fibroblasts. Here we show that Akt and the Akt-related kinase AKT2 are activated by PDGF. The activation was rapid and specific, and it was abrogated by mutations in the Akt Pleckstrin homology (PH) domain. The Akt activation was also shown to depend on PDGFR beta tyrosines Y740 and Y751, which bind phosphatidylinositol 3-kinase (PI 3-kinase) upon phosphorylation. Moreover, Akt activation was blocked by the PI 3-kinase-specific inhibitor wortmannin and the dominant inhibitory N17Ras. Conversely, Akt activity was induced following the addition of phosphatidylinositol-3-phosphate to Akt immunoprecipitates from serum-starved cells in vitro. These results identify Akt as a novel target of PI 3-kinase and suggest that the Akt PH domain may be a mediator of PI 3-kinase signaling.
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                Author and article information

                Contributors
                649144805@qq.com
                13709628221@163.com
                2432754368@qq.com
                2042632928@qq.com
                2816924339@qq.com , xuanchengfeng@outlook.com
                pengjuan1979@yahoo.com , pengjuan1979@gzhmu.edu.cn , jupeng@wakehealth.edu
                Journal
                Mol Biol Rep
                Mol. Biol. Rep
                Molecular Biology Reports
                Springer Netherlands (Dordrecht )
                0301-4851
                1573-4978
                24 April 2020
                24 April 2020
                2020
                : 47
                : 6
                : 4587-4629
                Affiliations
                [1 ]GRID grid.417009.b, ISNI 0000 0004 1758 4591, Department of Pathology, , The Third Affiliated Hospital of Guangzhou Medical University, ; 63 Duobao Road, Guangzhou, 510150 China
                [2 ]GRID grid.410737.6, ISNI 0000 0000 8653 1072, The Third Clinical School of Guangzhou Medical University, ; Guangzhou, 510150 China
                [3 ]Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
                [4 ]GRID grid.241167.7, ISNI 0000 0001 2185 3318, Department of Microbiology and Immunology, , Wake Forest School of Medicine, ; Winston-Salem, NC 27157 USA
                Article
                5435
                10.1007/s11033-020-05435-1
                7295848
                32333246
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: The National Natural Science Foundation of China
                Award ID: 81602631
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;
                Award ID: 2016A030310280
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009659, Guangzhou Medical University;
                Award ID: C195015021
                Award Recipient :
                Funded by: The Third Affiliated Hospital of Guangzhou Medical Uiversity
                Award ID: 2019A008
                Award Recipient :
                Categories
                Review
                Custom metadata
                © Springer Nature B.V. 2020

                Molecular biology

                pi3k, akt, pten, cancer, targeted therapy

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