The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells

• Published in: FEBS open bio Vol. 6; no. 12; pp. 1297 - 1309
• Main Authors: Ross, Thomas, Jakubzig, Bastian, Grundmann, Manuel, Massing, Ulrich, Kostenis, Evi, Schlesinger, Martin, Bendas, Gerd
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2016; John Wiley and Sons Inc; Wiley
• Subjects: Binding sites; Biosensors; Cancer; Cell adhesion & migration; Cell membranes; Cell migration; Cytotoxicity; Deactivation; Experiments; Fatty acids; Flow cytometry; Focal adhesion kinase; G protein‐coupled receptor; Immunoglobulins; integrin; Kinases; Lysophosphatidylcholine; lysophospholipid; Melanoma; Metastases; Metastasis; Motility; Phospholipids; Physiology; Plasma levels; Protein kinase C; Proteins; Solid tumors; Statistical analysis; Syndecan; Tumor cells; Germany; cancer; G protein‐coupled receptor; integrin; lysophospholipid; metastasis
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12152

Lysophophatidylcholine (LysoPC) is an abundant constituent in human plasma. Patients with malignant cancer diseases have attenuated LysoPC plasma levels, and thus LysoPC has been examined as a metabolic biomarker for cancer prediction. Preclinical studies have shown that solid tumor cells drastically degrade LysoPCs by incorporating their free fatty acids into cell membrane phospholipids. In this way, LysoPC C18:0 reduced the metastatic spread of murine melanoma B16.F10 cells in mice. Although membrane rigidification may have a key role in the attenuation of metastasis, evidence for this has yet to be shown. Therefore, the present study aimed to determine how LysoPC reduces the metastatic capacity of B16.F10 cells. Following cellular preincubation with LysoPC C18:0 at increasing concentrations and lengths of time, cell migration was most significantly attenuated with 450 μm LysoPC C18:0 at 72 h. Biosensor measurements suggest that, despite their abundance in B16.F10 cells, LysoPC‐sensitive G protein‐coupled receptors do not appear to contribute to this effect. Instead, the attenuated migration appears to result from changes in cell membrane properties and their effect on underlying signaling pathways, most likely the formation of focal adhesion complexes. Treatment with 450 μm LysoPC C18:0 activates protein kinase C (PKC)δ to phosphorylate syndecan‐4, accompanied by deactivation of PKCα. Subsequently, focal adhesion complex formation was attenuated, as confirmed by the reduced activity of focal adhesion kinase (FAK). Interestingly, 450 μm LysoPC C18:1 did not affect FAK activity, explaining its lower propensity to affect migration and metastasis. Therefore, membrane rigidification by LysoPC C18:0 appears to prevent the formation of focal adhesion complexes, thus affecting integrin activity as a key for metastatic melanoma spread. Lysophophatidylcholine (LysoPC) is strongly incorporated in tumor cell membranes, leading to membrane rigidification, PKCδ activation and finally SDC‐4 phosphorylation. SDC‐4 clustering and formation of a ternary complex are reduced which prevents focal complex formation of integrins and, ultimately, cell migration.