Interfering with the Ubiquitin-Mediated Regulation of Akt as a Strategy for Cancer Treatment

Abstract

The serine/threonine kinase Akt modulates the functions of numerous substrates, many of them being involved in cell proliferation and growth, metabolism, angiogenesis, resistance to hypoxia and migration. Akt is frequently deregulated in many types of human cancers, its overexpression or abnormal activation being associated with the increased proliferation and survival of cancer cells. A promising avenue for turning off the functionality of Akt is to either interfere with the K63-linked ubiquitination that is necessary for Akt membrane recruitment and activation or increase the K48-linked polyubiquitination that aims to target Akt to the proteasome for its degradation. Recent evidence indicates that targeting the ubiquitin proteasome system is effective for certain cancer treatments. In this review, the functions and roles of Akt in human cancer will be discussed, with a main focus on molecules and compounds that target various elements of the ubiquitination processes that regulate the activation and inactivation of Akt. Moreover, their possible and attractive implications for cancer therapy will be discussed.

LTe2 induces cell apoptosis in multiple myeloma by suppressing AKT phosphorylation at Thr308 and Ser473

“…Furthermore, in combination with RNA-seq we found that indole oligomers could inhibit MM cell proliferation by suppressing AKT phosphorylation. AKT activation and degradation are known to be involved in various biological responses, such as cell survival, proliferation, protein translation, and metabolism ( 33 – 35 ). Many oncogenes and proto-oncogenes are protein kinases that undergo phosphorylation, and their activation often contributes to tumorigenesis ( 36 , 37 ).…”

Protein Stability Regulation in Osteosarcoma: The Ubiquitin-like Modifications and Glycosylation as Mediators of Tumor Growth and as Targets for Therapy

“…AKT exists in three highly homologous isoforms that can be ubiquitinated by different E3 ligases. Depending on the type of ubiquitination, this may result in the activation of the pathway, via K63 ubiquitination, or its inhibition via K48 ubiquitination [ 42 ]. Among all the AKT-activating E3 ligases, two are overexpressed in osteosarcoma.…”

Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice

“…As a proto-oncogene, Akt plays a crucial role in various biological processes. Disruptions to the Akt signaling pathway are associated with multiple human diseases, such as cancer, cardiovascular disease, and neurological disorders [ 24 , 25 ]. And it’s reported that phosphorylated Akt could upregulate the expression of nuclear factor E2-related factor 2 (Nrf2), which was involved in antioxidant and cytoprotective functions, inhibition of inflammation, and modulation of microglial functional phenotype [ 26 – 29 ].…”