Akt: a key transducer in cancer

Abstract

Growth factor signaling plays a pivotal role in diverse biological functions, such as cell growth, apoptosis, senescence, and migration and its deregulation has been linked to various human diseases. Akt kinase is a central player transmitting extracellular clues to various cellular compartments, in turn executing these biological processes. Since the discovery of Akt three decades ago, the tremendous progress towards identifying its upstream regulators and downstream effectors and its roles in cancer has been made, offering novel paradigms and therapeutic strategies for targeting human diseases and cancers with deregulated Akt activation. Unraveling the molecular mechanisms for Akt signaling networks paves the way for developing selective inhibitors targeting Akt and its signaling regulation for the management of human diseases including cancer.

The Cytotoxic Cardiac Glycoside (−)-Cryptanoside A from the Stems ofCryptolepis dubiaand Its Molecular Targets

“…As a result, these stressed cells activate Akt to enhance their survival, and thus the expression of p-Akt was increased after MDA-MB-231 cells were treated by 1 at 0.5 μM for 5 h. Consistently, the expression of Akt was also increased after cells were treated by 1 at high concentrations for 72 h, from which a small proportion of cells survived (Figures 4 and 5). Activated Akt can result in activation of NF-κB, 49 which controls DNA transcription, cytokine production, and cell survival, and connects infection, cancer, and cancer immunity, and thus promotes tumorigenesis and modulates the cancer response to therapy. 52,53 NF-κB supports cancer cell proliferation and tumor growth through the transcription of antiapoptotic proteins, and thus inhibition of NF-κB can be of benefit to cancer treatment.…”

“…Akt, also named as protein kinase B (PKB), is a set of three serine/threonine-specific protein kinases (Akt1, Akt2, and Akt3) that play a key role in cell survival, cell cycle, metabolism, autophagy, and angiogenesis. Akt regulates many downstream proteins, including NF-κB, Bcl-2, TFEB, MDM2, and Wnt, and thus becomes a dependent effector for cell survival, and activation of Akt can promote tumor growth . Also, Akt is a major protein in PI3K/Akt/mTOR signaling, and several Akt inhibitors have been thus far evaluated in clinical trials for the development of new anticancer agents, even though some adverse effects such as hyperglycemia and hyperinsulinemia have been observed for them .…”

LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway

“…In general, cell cycle is primarily regulated by cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors such as P21 and P27. AKT is known to promote cell growth and proliferation by inhibiting P21 and P27 and regulating the activities of Cyclin D1 and CDK4 at G1/S cell cycle checkpoint [31][32][33][34][35]. P21 and P27 bind CDKs, inhibiting enzymatic activities of CDKs and arresting cell cycle at G1 phase.…”

Targeted therapy based on ubiquitin-specific proteases, signalling pathways and E3 ligases in non-small-cell lung cancer

“…AKT plays an important role in tumor growth and development, such as ovarian, breast and gastric cancers ( 121 – 123 ). K63-linked polyubiquitination of AKT at lysine 8 and 14, which is mediated by the E3 ligase TRAF6 or SKP2, can localise AKT to the cell membrane, thereby resulting in AKT activation and enhanced intracellular signalling ( 124 ).…”