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 BRAFV600E 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.

Proteomic Changes in the Monolayer and Spheroid Melanoma Cell Models of Acquired Resistance to BRAF and MEK1/2 Inhibitors

“…Aggressive cancer tissues, such as melanoma and esophageal, have also exhibited amplification in the PI3K pathway and high levels of autophagy. , Inhibitors of the PI3K pathway or autophagy have been suggested in combination with ERK1/2 pathway inhibition as an approach to treat melanoma. , While PLX/AZD-resistant monolayers showed activation of the PI3K pathway (Tables and ), only PLX/AZD-resistant spheroid cultures demonstrated enhanced autophagy markers (Table ). In addition, decreased INPP5F (inositol polyphosphate-5-phosphatase F) in both spheroid and monolayer cell models (Table S1) is an indicator of increased PI3K activity. , Figure also suggests increased sphingolipid hydrolysis, which has been shown to increase ceramide levels in cells and promote autophagosomic membrane maturation via ATG9A (Table ).…”

“…36 Aggressive cancer tissues, such as melanoma and esophageal, have also exhibited amplification in the PI3K pathway and high levels of autophagy. 121,122 Inhibitors of the PI3K pathway or autophagy have been suggested in combination with ERK1/2 pathway inhibition as an approach to treat melanoma. 123,124 While PLX/AZD-resistant monolayers showed activation of the PI3K pathway (Tables 2 and 3), only PLX/AZD-resistant spheroid cultures demonstrated enhanced autophagy markers (Table 8).…”

Genetic silencing of AKT induces melanoma cell death

“…The striking success of inhibitors of BRAF V600E >MEK>ERK signaling in patients with BRAF -mutated melanoma begs the question as to the utility of additional pathway-targeted agents in this disease, either as single agents or in combination therapy, in which patients might be stratified using predictive biomarkers. Examples include the possible use in melanoma of: CDK4/6 inhibitors in tumors with INK4A silencing; MDM2 inhibitors in tumors that express normal TP53 or; PI3K or AKT inhibitors in tumors with alterations in NRAS, RAC1, PIK3CA, AKT1-3 or PTEN (31). However to date, despite compelling preclinical data supporting their clinical deployment, the use of PI3K or AKT inhibitors in the treatment of melanoma has been confounded by issues of toxicity, lack of efficacy or both (32,33).…”

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long‐chain acyl‐coenzyme A synthase 5

“…PI3K family has 14 isoforms responsible for the phosphorylation of 3′ hydroxyl of the inositol ring of phosphatidylinositides to produce PI3K-lipids and modulate the major stream of intracellular signals. 10 Lysophosphatidylcholine (lysoPC) is derived from PCs by phospholipase A 2 , degraded to glycerophosphocholine and free FA (FFA) and catalyzed by lysophospholipase A1 and A2 extracellularly. 11 The resulting FFAs can be taken up and incorporated into membrane phospholipids and neutral lipids.…”

“…PI3K family has 14 isoforms responsible for the phosphorylation of 3′ hydroxyl of the inositol ring of phosphatidylinositides to produce PI3K‐lipids and modulate the major stream of intracellular signals. 10 …”