OverAKT3: Tumor progression and chemoresistance
作者： Ping Ji , Kristen M Turner , Wei Zhang
DOI: 10.1080/15384101.2015.1046787
关键词:
摘要: Akt3 is one of 3 closely related serine/threonine-protein kinases in the Akt family (Akt1, Akt2, and Akt3). among most hyperactivated oncogenes human cancer, regulating key cellular functions such as growth, proliferation, migration, invasion, angiogenesis, metabolism, survival.1,2 Studies evaluating effect isoform gene knockout on mouse development found that loss Akt1 increased perinatal mortality affected overall growth mice. Akt2 led to a diabetic phenotype but otherwise normal development, whereas both brain testes size. Tissue distribution isoforms also gives an indication their functional roles under circumstances: are ubiquitously expressed, while expression mostly restricted testes. In recent years, it has become evident more important than gliomagenesis progression.3 The first evidence was reported which mediate invasion rat C6 glioma cells; inhibition prolonged survival orthotopic model. Subsequent reports have shown possibly Akt3, for progression maintenance, does not play major role.3 More specifically, knockdown EGFR U87MG-EGFRvIII cells apoptosis, reduced tumor nude This same result observed upon or Akt3. Another study (but Akt1) decreased Bad phosphorylation caspase-9 caspase-3 activity, suggesting these cell viability through regulation mitochondrial membrane potential.3 A paper evaluated by injecting transformed astrocytes into brains mice rapidly develop high-grade astrocytoma. resulting had defined genetic background included p53 with EGFRvIII expression, without PTEN; proliferation PTEN wild-type astrocytes, combined multiple needed inhibit PTEN-null astrocytes. In addition, displayed unique enabling anchorage-independent invasion.4 Our RCAS/Ntv-a glia-specific model revealed that, isoforms, highest capacity promote development.5 The pathway signaling pathways glioma, activation status correlates grade. kinase downstream mediator PI3K pathway, recruitment plasma via its PH (pleckstrin homology) domain. anchoring proximity enables PDK1 (3-phosphoinositide-dependent protein 1) phosphorylate Thr-308 mTORC2 (mammalian target rapamycin complex 2) Ser-473. Once phosphorylated thus activated, governs over 100 substrates. The three shared well distinct cancer cells. function characterized. Isoform-specific dependent localization targets. For example, AEG1-Akt2 interaction stabilization at S474, cascades enable survival.6 Phosphorylation TBX3 promotes stability, nuclear localization, transcriptional repression E-cadherin contributes migration invasion. Specific palladin, actin bundling protein, migration. Conversely, been breast epithelial-to-mesenchymal transition mir-200 modulation Snail1 promoter. controls biogenesis autophagy export CRM-1.7 Our current work shows sensitive other factor stimulation, including EGF PDGFB. We further discovered predominant modification nucleus. believe role therapeutic resistance (Fig. 1). plays critical DNA double strand break repair radiotherapy chemotherapy. Thus some glioblastomas standard treatment approaches may be due amplification/hyperactivation capacity. Given dominant player aids therapy, inhibitors should developed tested specifically block function. suggest investigated combination therapy tumors amplified Figure 1. Akt3 (DSB) repair. nucleus cells, signature genes associated driven involved ... In conclusion, resistance. genomic amplification wide range cancers, glioblastoma, predominantly located our model, we when Akt3-induced pathways. Moreover, homologous recombination non-homologous end joining. Targeting and/or protein(s) might effective strategy glioma.
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