Role of Akt/Protein Kinase B in Cancer Metastasis

Abstract

Metastasis is a critical step in the process of carcinogenesis and a vast majority of cancer-related mortalities result from metastatic disease that is resistant to current therapies. Cell migration and invasion are the first steps of the metastasis process, which mainly occurs by two important biological mechanisms, i.e., cytoskeletal remodelling and epithelial to mesenchymal transition (EMT). Akt (also known as protein kinase B) is a central signalling molecule of the PI3K-Akt signalling pathway. Aberrant activation of this pathway has been identified in a wide range of cancers. Several studies have revealed that Akt actively engages with the migratory process in motile cells, including metastatic cancer cells. The downstream signalling mechanism of Akt in cell migration depends upon the tumour type, sites, and intracellular localisation of activated Akt. In this review, we focus on the role of Akt in the regulation of two events that control cell migration and invasion in various cancers including head and neck squamous cell carcinoma (HNSCC) and the status of PI3K-Akt pathway inhibitors in clinical trials in metastatic cancers.

Keywords: Akt; EMT; HNSCC; cancer; cytoskeletal remodelling; metastasis.

Figure 1

Metastasis cascade. Tumour cells proliferate uncontrollably and eventually lose their adhesive phenotype. Tumour cells then migrate and invade into surrounding tissues induced by the tumour microenvironment and intravasate to lymphatic and blood vessels. Circulating tumour cells then extravasate, enter into another tissue, and form micro-metastases at the secondary site.

Figure 2

PI3K-Akt signalling pathway. Upon ligand binding, conformational changes occur in the receptor tyrosine kinase (RTK), the PI3 kinases are then activated by RTK and translocate to the plasma membrane. Activated PI3K then converts PIP2 to PIP3. Pleckstrin homology (PH) domain containing protein, Akt then translocate to the membrane, bind to PIP3, and phosphorylate at the Threonine 308 residue by PDK1. Akt translocates back to the cytoplasm and is phosphorylated further at Serine 473 and Threonine 450 residues by mTORC2. Activated Akt is responsible for initiating various cellular activities such as proliferation, protein synthesis, autophagy, cell survival, etc.

Figure 3

Partial epithelial to mesenchymal transition (p-EMT) and full EMT with associated biological markers. When appropriate signalling pathways are switched on, non-polarised, cobblestone-shaped epithelial cells lose their cell–cell contacts and change to mesenchymal-type motile cells. Extracellular matrix degradation enzymes, MMPs, then degrade the ECM and cells migrate through the basal lamina. This event can be detected at a molecular level by a reduction in levels of epithelial markers such as E-cadherin, b-catenin, cytokeratin, etc., and higher levels of mesenchymal markers such as vimentin, Snail, and Twist, etc. p-EMT cells also exists in a meta-stable, intermediary state between the epithelial and mesenchymal poles, suggesting this as a spectrum instead of a switch.

Figure 4

The role of Akt in the metastasis process. Cellular motility or migration is the first step of the tumour cell metastatic process. Cytoskeletal remodelling and/or epithelial to mesenchymal transition are the two cellular events that are responsible for cell migration. Akt plays significant roles in cellular migration by controlling various downstream substrates which regulate these two events. The function of Akt has been found to be cell type, tumour type, and site dependent.