Secreted Phospholipases A2: Drivers of Inflammation and Cancer

Abstract

Secreted phospholipase 2 (sPLA2) is the largest family of phospholipase A2 (PLA2) enzymes with 11 mammalian isoforms. Each sPLA2 exhibits different localizations and specific properties, being involved in a very wide spectrum of biological processes. The enzymatic activity of sPLA2 has been well described; however, recent findings have shown that they could regulate different signaling pathways by acting directly as ligands. Arachidonic acid (AA) and its derivatives are produced by sPLA2 in collaboration with other molecules in the extracellular space, making important impacts on the cellular environment, being especially relevant in the contexts of immunity and cancer. For these reasons, this review focuses on sPLA2 functions in processes such as the promotion of EMT, angiogenesis, and immunomodulation in the context of tumor initiation and progression. Finally, we will also describe how this knowledge has been applied in the search for new sPLA2 inhibitory compounds that can be used for cancer treatment.

Keywords: EMT; arachidonic acid; phospholipases; sPLA2; tumor microenvironment.

Figure 1

Metabolic products of arachidonic acid (AA). AA is released from membrane phospholipids by phospholipase A2 (PLA2) and metabolized by three main enzyme families: cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP450). COX-1 and COX-2 convert AA into prostaglandins (PG) D, I, E, A, and F2α, and thromboxanes A2 (TXA2). LOX catalyze the formation of hydroperoxyeicosatetraenoic acids (HpETE) and hydroxyeicosatetraenoic acids (HETE), leukotrienes (LT) A, B, C, D, and E, and lipoxins (LX) A and B. Lastly, CYP450 converts AA in epoxyeicosatrienoic acids (EET) and HETE. Dashed arrows represent each metabolite’s role in inflammation, angiogenesis, metastasis, proliferation, and immune modulation.

Figure 2

Signaling networks that regulate epithelial–mesenchymal transition (EMT) activated by secreted phospholipases A2 (sPLA2). sPLA2 can activate EMT signaling pathways directly by engaging with sPLA2A-binding proteins (sPLA2A-BP) and being translocated to the cytoplasm, or by producing arachidonic acid and downstream metabolites (AA met). Transforming growth factor β (TGF-β), growth receptors and tumor necrosis factor α (TNFα) signaling pathways can induce EMT by the activation of the transcription factors (TF) SNAI1, ZEB1/2, TWIST, and SLUG. TGF-β induces EMT by the phosphorylation of Smad2 and Smad3, which localize to the nucleus with Smad4 to activate EMT TF. Several growth factors that act through tyrosine kinase receptors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), promote EMT thought the RAS-Mitogen-activated protein kinase (MAPK)/ERK signaling cascade or the Phosphatidylinositol 3-kinase/Protein kinase B (PI3K)/Akt axis, which ultimately activate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). TNFα also activates the NF-κB pathway. Finally, Wnt stabilizes β-catenin, which translocates to the nucleus to activate ZEB1 and SNAI1 directly.