Akt2 and Akt3 play a pivotal role in malignant gliomas

Abstract

Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBa, Akt2/PKBb, and Akt3/PKBg and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knockdown and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas.Keywords: Akt2, Akt3, apoptosis, glioma, protein and gene expression profile M alignant glioma, the most common primary brain tumor in adults, carries a poor prognosis. The median survival of patients with highgrade glioma (World Health Organization [WHO] grade III or IV) is 10 -30 months despite multimodal treatment with surgery, radiation, and chemotherapy. 1 Malignant gliomas develop as a result of the stepwise accumulation of alterations in genes regulating cell proliferation, differentiation, and apoptosis. The amplification and mutation of epidermal growth factor receptor, a transmembrane receptor with intrinsic tyrosine kinase activity, have been documented. Tyrosine kinase receptors activate several signaling pathways including mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K). The activation of tyrosine kinase receptor-mediated signaling pathways plays an important role in the tumorigenesis and maintenance of malignant human gliomas.2,3 The constitutively activated PI3K/Akt pathway delivers major survival signals to glioblastoma multiforme (GBM) and other cancer cells.4 -7 Akt, with its serine -threonine protein kinase activity, is a major downstream effector of the PI3K pathway, and the ectopic expression of Akt induces cell survival and malignant transformation. On the other hand, the inhibition of Akt activity stimulates apoptosis in a range of mammalian cells. 8 -10 Akt is activated in 70% of gliomas and is usually associated wit...

Akt1 and Akt3 Exert Opposing Roles in the Regulation of Vascular Tumor Growth

“…Akt3 is expressed at lower levels in vascular tumors than in normal blood vessels. Such a scenario has also been observed in malignant glioma, in which the expression of Akt3 is lower in the tumor than in normal brain tissue; however, the remaining Akt3 has kinase activity (36). This suggests that although the level of endogenous Akt3 is reduced, it still retains the functional capacity as an active kinase.…”

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

“…Mice lacking Akt1 have small body size, mice lacking Akt2 show a diabetic phenotype, and mice lacking Akt3 have reduced brain size (Cho et al 2001a,b, Easton et al 2005, Tschopp et al 2005. In melanoma cells, Akt3 was found to be the principal Akt isoform involved in tumor development, while in malignant glioma, Akt2 was shown to promote cell migration, invasion, and viability (Stahl et al 2004, Zhang et al 2009, Mure et al 2010. In breast cancer, Akt1, though playing an important role in tumor induction, inhibits metastasis while Akt2 exhibits promigratory effects and facilitates proliferation and cell survival (Hutchinson et al 2004, Dillon et al 2009).…”

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

“…The first studies were reported on Akt2 only, which was found to mediate invasion in rat C6 glioma cells (13), and inhibition of Akt2 prolonged survival in an orthotopic rat model (14). Subsequent reports have found that Akt2, and possibly Akt3, are important for disease progression and maintenance, whereas Akt1 does not play a major role (15,16). Another study in transformed mouse astrocytes indicate that Akt isoform function is potentially modulated by the genetic landscape of the tumor (17).…”