The role of PI3'-lipid signalling in melanoma initiation, progression and maintenance

Abstract

Phosphatidylinositol-3'-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3' hydroxyl (OH) of the inositol ring of phosphatidylinositides (PI). Through their downstream effectors, PI3K generated lipids (PI3K-lipids hereafter) such as PI(3,4,5)P₃ and PI(3,4)P₂ regulate myriad biochemical and biological processes in both normal and cancer cells including responses to growth hormones and cytokines; the cell division cycle; cell death; cellular growth; angiogenesis; membrane dynamics; and autophagy and many aspects of cellular metabolism. Engagement of receptor tyrosine kinase by their cognate ligands leads to activation of members of the Class I family of PI3'-kinases (PI3Kα, β, δ & γ) leading to accumulation of PI3K-lipids. Importantly, PI3K-lipid accumulation is antagonized by the hydrolytic action of a number of PI3K-lipid phosphatases, most notably the melanoma suppressor PTEN (lipid phosphatase and tensin homologue). Downstream of PI3K-lipid production, the protein kinases AKT1-3 are believed to be key effectors of PI3'-kinase signalling in cells. Indeed, in preclinical models, activation of the PI3K→AKT signalling axis cooperates with alterations such as expression of the BRAF^V600E oncoprotein kinase to promote melanoma progression and metastasis. In this review, we describe the different classes of PI3K-lipid effectors, and how they may promote melanomagenesis, influence the tumour microenvironment, melanoma maintenance and progression to metastatic disease. We also provide an update on both FDA-approved or experimental inhibitors of the PI3K→AKT pathway that are currently being evaluated for the treatment of melanoma either in preclinical models or in clinical trials.

Keywords: biomarkers; cancer; melanogenesis; melanoma.

FIGURE 1

Phosphatidylinositol-3’-kinase signalling pathway is a vital regulator of proliferation, metabolism, angiogenesis, apoptosis, differentiation and cell cycle arrest

FIGURE 2

There are three distinct classes of PI3’ kinases characterized according to their structure and lipid substrate specificity. The most extensively studied PI3Ks are the Class I PI3Ks, which consist of catalytic and regulatory subunits

FIGURE 3

Phosphatidylinositol-3’-kinase signalling network is dynamic and complex in nature. This signal transduction pathway is a critical regulator of cellular growth, proliferation, survival and metabolism in response to extracellular signals, such as receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), RAS proteins and cell-cell contact. Feedback loops originate from distant elements of the same pathway or from other pathways, such as the MAPK pathway depicted here. Melanoma cells exhibit plasticity and upregulate positive and negative-feedback mechanisms in response to signalling through the PI3’-kinase pathway thereby restraining the activity of upstream nodes