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Open AccessArticle

Cytosolic Phospholipase A2 Alpha Regulates TLR Signaling and Migration in Metastatic 4T1 Cells

1
Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, P.O. Box 8905, 7491 Trondheim, Norway
2
Center for Oral Health Services and Research (TkMidt), 7030 Trondheim, Norway
3
Department of Biology, Norwegian University of Science and Technology, Realfagbygget, 7491 Trondheim, Norway
4
Department of Health Sciences, Nord University, P.O. Box 1490, 8049 Bodø, Norway
*
Authors to whom correspondence should be addressed.
Shared senior authorship.
Int. J. Mol. Sci. 2019, 20(19), 4800; https://doi.org/10.3390/ijms20194800
Received: 9 September 2019 / Accepted: 14 September 2019 / Published: 27 September 2019
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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. View Full-Text
Keywords: eicosanoids; cPLA2 inhibitor; migration; metastasis; 4T1; 67NR; triple-negative breast cancer; Toll-like receptor eicosanoids; cPLA2 inhibitor; migration; metastasis; 4T1; 67NR; triple-negative breast cancer; Toll-like receptor
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Tunset, H.M.; Feuerherm, A.J.; Selvik, L.-K.M.; Johansen, B.; Moestue, S.A. Cytosolic Phospholipase A2 Alpha Regulates TLR Signaling and Migration in Metastatic 4T1 Cells. Int. J. Mol. Sci. 2019, 20, 4800.

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