Metastatic disease is the leading cause of death in breast cancer patients. Disrupting the cancer cell’s ability to migrate may be a strategy for hindering metastasis. Cytosolic phospholipase A2 α (cPLA2α), along with downstream proinflammatory and promigratory metabolites, has been implicated in several aspects of tumorigenesis, as well as metastasis, in various types of cancer. In this study, we aim to characterize the response to reduced cPLA2α activity in metastatic versus non-metastatic cells. We employ an isogenic murine cell line pair displaying metastatic (4T1) and non-metastatic (67NR) phenotype to investigate the role of cPLA2α on migration. Furthermore, we elucidate the effect of reduced cPLA2α activity on global gene expression in the metastatic cell line. Enzyme inhibition is achieved by using a competitive pharmacological inhibitor, cPLA2α inhibitor X (CIX). Our data show that 4T1 expresses significantly higher cPLA2α levels as compared to 67NR, and the two cell lines show different sensitivity to the CIX treatment with regards to metabolism and proliferation. Inhibition of cPLA2α at nontoxic concentrations attenuates migration of highly metastatic 4T1 cells, but not non-metastatic 67NR cells. Gene expression analysis indicates that processes such as interferon type I (IFN-I) signaling and cell cycle regulation are key processes regulated by cPLA2a in metastatic 4T1 cells, supporting the findings from the biological assays. This study demonstrates that two isogenic cancer cell lines with different metastatic potential respond differently to reduced cPLA2α activity. In conclusion, we argue that cPLA2α is a potential therapeutic target in cancer and that enzyme inhibition may inhibit metastasis through an anti-migratory mechanism, possibly involving Toll-like receptor signaling and type I interferons.

Chronic kidney disease (CKD) is a significant global health burden and a leading cause of death in the United States. Chronic inflammation contributes to fibrosis and CKD progression. Here, we present evidence that a key pro-inflammatory group IVA phospholipase A₂ enzyme (cPLA₂α) is critical to the development of kidney inflammation and fibrosis and can be targeted pharmacologically to attenuate CKD in animal models. Consistent with a role in human disease, overexpression of cPLA₂α is seen in kidneys from patients suffering from CKD, and its expression is inversely correlated with the glomerular filtration rate. Genetic ablation of cPLA₂α or inhibition with 1-octadeca-3,6,9,12,15-pentaenylsulfanyl-propan-2-one (AVX002) reduced inflammation and ameliorated renal fibrosis in mouse and rat disease models. In addition, reduced levels of eleven arachidonic acid-derived plasma eicosanoids demonstrated inhibitor effectiveness and specificity. Furthermore, AVX002 dose-dependently reduced kidney fibroblast production of profibrotic, pro-inflammatory components leading to progressive fibrotic kidney failure. In conclusion, our results strongly suggest that inhibition of cPLA₂α holds promise as a novel therapeutic strategy for renal fibrosis and chronic kidney disease.