The Akt isoforms, their unique functions and potential as anticancer therapeutic targets

Abstract

Akt (also known as protein kinase B or PKB) is the major downstream nodal point of the PI3K signaling pathway. This pathway is a promising anticancer therapeutic target, because constitutive activation of the PI3K-Akt pathway is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies. The Akt serine/threonine kinase regulates diverse cellular functions including cell growth, proliferation, glucose metabolism, and survival. Although all three known Akt isoforms (Akt1-3) are encoded by separate genes, their amino acid sequences show a high degree of similarity. For this and other reasons, it has long been assumed that all three Akt isoforms are activated in the same way, and their functions largely overlap. However, accumulating lines of evidence now suggest that the three Akt isoforms might have unique modes of activation and many distinct functions. In particular, it has recently been found that the Akt isoforms are localized at different subcellular compartments in both adipocytes and cancer cells. In this review, we highlight the unique roles of each Akt isoform by introducing published data obtained from both in vitro and in vivo studies. We also discuss the significant potential of the Akt isoforms as effective anticancer therapeutic targets.

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

“…Although Akt isoforms are encoded by different genes on chromosomes 14q32, 19q13 and 1q44, respectively, their amino acid sequences share approximately 80% similarity [27]. Akt isoforms each contain three similar domains -pleckstrin homology, kinase and regulatory domains -and the isoforms are localized in distinct subcellular compartments [15,28]. Akt isoforms have different functions in normal physiology and development [29].…”

“…As it is known so far, Akt3, localized in the nucleus and nuclear membrane, is essential for the attainment of normal brain size [34]. Due to the distinct subcellular localization of Akt isoforms in cancer cells [15,28], the current model for the role of PI3K, PDK1 and PDK2 in Akt activation might only be applicable to Akt1.…”

Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model

“…This was confirmed in our BALB-CTA, where Akt phosphorylation was decreased dose-dependently by OSI-906 in both the non-transformed as well as the transformed BALB/c cells. It is known that an overexpression of the three different Akt isoforms can promote proliferation of cancer cells and they have been found deregulated in several cancers54. Whether the overall Akt activity rather than the phosphorylation of specific Akt isoforms is crucial for the transformation process has to be elucidated further.…”

A Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as Potential Chemotherapeutic Agent: From Synthesis to In Vivo Studies

“…89 Despite their high sequence similarity, they exhibit unique functions. 90 Akt-1 was found to be involved in the regulation of cell proliferation, transformation and tumour metastasis. 90 In this study, we assessed the Overall, Ru-sq displayed better activity than cisplatin in 2D and 3D cell cultures as well as for some conditions used in vivo.…”

“…90 Akt-1 was found to be involved in the regulation of cell proliferation, transformation and tumour metastasis. 90 In this study, we assessed the Overall, Ru-sq displayed better activity than cisplatin in 2D and 3D cell cultures as well as for some conditions used in vivo. In conclusion, in this work, we could demonstrate the promising potential expressed by Ru-sq as chemotherapeutic agent against cancer.…”