Genetic modelling of the PTEN/AKT pathway in cancer research

Experimental Therapeutics Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Clinical and Translational Oncology (Impact Factor: 2.08). 11/2008; 10(10):618-27. DOI: 10.1007/s12094-008-0262-1
Source: PubMed


The focus on targeted therapies has been fuelled by extensive research on molecular pathways and their role in tumorigenesis. Novel models of human cancer have been created to evaluate the role of specific genes in the different stages of cancer. Currently, mouse modelling of human cancer is possible through the expression of oncogenes, specific genetic mutations or the inactivation of tumour suppressor genes, and these models have begun to provide us with an understanding of the molecular pathways involved in tumour initiation and progression at the physiological level. Additionally, these mouse models serve as an excellent system to evaluate the efficacy of currently developed molecular targeted therapies and identify new potential targets for future therapies. The PTEN/AKT pathway is implicated in signal transduction through tyrosine kinase receptors and heterotrimeric G protein-linked receptors. Deregulation of the PTEN/AKT pathway is a common event in human cancer. Despite the abundant literature, the physiological role of each element of the pathway has begun to be uncovered thanks to genetically engineered mice. This review will summarise some of the key animal models which have helped us to understand this signalling network and its contribution to tumorigenesis.

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Available from: Oliver Renner, Oct 04, 2015
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    • "Many studies have found that pentacyclic triterpene compounds induced apoptosis through regulating apoptosisrelated protein (Liu et al. 2007; Zhang et al. 2007; Zheng et al. 2006). Akt/PKB, a serine threonine kinase which is a critical signaling molecule promoting cell growth and survival pathways, is frequently dysregulated in many cancers and diabetes (Carnero et al. 2008; Gershtein et al. 2007; Mahajan and Mahajan 2012; Renner et al. 2008). To date, three members of the Akt family denominated Akt1, Akt2, and Akt3 have been identified. "
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    ABSTRACT: Oleanolic acid (OA) derivatives exhibit numerous pleiotropic effects in many cancers. The present study aimed to investigate the molecular mechanisms of 5'-amino-oleana-2,12-dieno[3,2-d]pyrimidin-28-oic acid (compound 4) and oleana-2,12-dieno[2,3-d]isoxazol-28-oic acid (compound 5) inducing apoptosis in human leukemia K562 cell. We investigated the effects of the compounds on K562 cell growth, apoptosis and cell cycle. The compounds showed strong inhibitory effects on K562 cell viability in a dose-dependent manner determined by the 3-(4,5-dimethylthiazoyl)-2,5-diphenyltetrazolium bromide assay and significantly increased chromatin condensation and apoptotic bodies in K562 cells. Flow cytometry assay suggested that the compounds induced inhibition of K562 cell proliferation associated with G1 phase arrest. In addition, the compounds inhibited Akt1 recruiting to membrane in CHO cells which express Akt1-EGFP constitutively and down-regulated the expression of pAkt1 in K562 cell. These results suggested that the compounds can efficiently inhibit proliferation and induce apoptosis perhaps involved in inactivation of Akt1. The OA derivatives may be potential chemotherapeutic agents for the treatment of human cancer.
    Cytotechnology 04/2014; 67(5). DOI:10.1007/s10616-014-9722-3 · 1.75 Impact Factor
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    • "In addition, due to lack of control of the signaling pathways that mediate apoptosis and migration, such as Ras/phosphoinositide 3-kinase (PI3K)/AKT, it plays a fundamental role in tumor cell survival and proliferation and metastasis. PTEN is frequently deficient in several malignancies because of mutations or epigenetic changes [68,69] In addition evidences has also been provided supporting that CpG islands of the PTEN promoter are methylated in several type of human cancers, such as endometrial carcinoma [70], gastric [71], non-small-cell lung carcinoma [72] and cervical cancer [73]. Kurasawa et al. analyzed the immunohistochemical expression of PTEN in 113 OSCC and 9 OSCC cell-lines [47]. "
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    ABSTRACT: Squamous cell carcinoma of the oral region (OSCC) is one of the most common and highly aggressive malignancies worldwide, despite the fact that significant results have been achieved during the last decades in its detection, prevention and treatment. Although many efforts have been made to define the molecular signatures that identify the clinical outcome of oral cancers, OSCC still lacks reliable prognostic molecular markers. Scientific evidence indicates that transition from normal epithelium to pre-malignancy, and finally to oral carcinoma, depends on the accumulation of genetic and epigenetic alterations in a multistep process. Unlike genetic alterations, epigenetic changes are heritable and potentially reversible. The most common examples of such changes are DNA methylation, histone modification, and small non-coding RNAs. Although several epigenetic changes have been currently linked to OSCC initiation and progression, they have been only partially characterized. Over the last decade, it has been demonstrated that especially aberrant DNA methylation plays a critical role in oral cancer. The major goal of the present paper is to review the recent literature about the epigenetic modifications contribution in early and later phases of OSCC malignant transformation; in particular we point out the current evidence of epigenetic marks as novel markers for early diagnosis and prognosis as well as potential therapeutic targets in oral cancer.
    International Journal of Molecular Sciences 12/2012; 13(2):2331-53. DOI:10.3390/ijms13022331 · 2.86 Impact Factor
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    • "In T-ALL patients and hematological malignant cell lines, miR-19 was significantly upregulated, and its target genes such as PTEN, HOXA, BCL2L11, CYLD and NOTCH1 were repressed. PTEN is a tumor suppress gene and its down-regulation will activate the PI3K/AKT signaling pathway in cancers (56,57). In T-ALL patients, post-translational inactivation of PTEN would cause incontrollable proliferation of T cell (58,59). "
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    ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. The understanding of its gene expression regulation and molecular mechanisms still remains elusive. Started from experimentally verified T-ALL-related miRNAs and genes, we obtained 120 feed-forward loops (FFLs) among T-ALL-related genes, miRNAs and TFs through combining target prediction. Afterwards, a T-ALL miRNA and TF co-regulatory network was constructed, and its significance was tested by statistical methods. Four miRNAs in the miR-17-92 cluster and four important genes (CYLD, HOXA9, BCL2L11 and RUNX1) were found as hubs in the network. Particularly, we found that miR-19 was highly expressed in T-ALL patients and cell lines. Ectopic expression of miR-19 represses CYLD expression, while miR-19 inhibitor treatment induces CYLD protein expression and decreases NF-κB expression in the downstream signaling pathway. Thus, miR-19, CYLD and NF-κB form a regulatory FFL, which provides new clues for sustained activation of NF-κB in T-ALL. Taken together, we provided the first miRNA-TF co-regulatory network in T-ALL and proposed a model to demonstrate the roles of miR-19 and CYLD in the T-cell leukemogenesis. This study may provide potential therapeutic targets for T-ALL and shed light on combining bioinformatics with experiments in the research of complex diseases.
    Nucleic Acids Research 02/2012; 40(12):5201-14. DOI:10.1093/nar/gks175 · 9.11 Impact Factor
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