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首页> 外文期刊>FEBS Open Bio >The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells
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The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells

机译：饱和溶血磷脂酰胆碱减弱黑素瘤细胞转移能力的分子机制

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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.
机译：磷脂酰胆碱（LysoPC）是人血浆中的丰富成分。具有恶性癌症疾病的患者的LysoPC血浆水平降低，因此LysoPC已作为癌症预测的代谢生物标记物进行了检查。临床前研究表明，实体瘤细胞通过将LysoPC的游离脂肪酸掺入细胞膜磷脂中，从而彻底降解LysoPC。这样，LysoPC C18：0减少了小鼠黑色素瘤B16.F10细胞在小鼠中的转移扩散。尽管膜硬化可能在转移的减弱中起关键作用，但尚未证明这一点。因此，本研究旨在确定LysoPC如何降低B16.F10细胞的转移能力。用浓度和时间延长的LysoPC C18：0进行细胞预孵育后，细胞迁移在72 h时被450μmLysoPC C18：0衰减最明显。生物传感器的测量表明，尽管它们在B16.F10细胞中含量很高，但LysoPC敏感的G蛋白偶联受体似乎并未对此产生影响。相反，减弱的迁移似乎是由于细胞膜特性的变化及其对基础信号通路的影响所致，最有可能是粘着斑复合物的形成。用450μmLysoPC C18：0处理可激活蛋白激酶C（PKC）δ磷酸化syndecan-4，并伴随PKCα失活。随后，如通过粘着斑激酶（FAK）活性降低所证实的，粘着斑复合物的形成被减弱。有趣的是，450μmLysoPC C18：1不会影响FAK活性，这说明其影响迁移和转移的倾向较低。因此，通过LysoPC C18：0进行的膜硬化似乎可以防止形成粘着斑复合物，从而影响整联蛋白的活性，这是转移性黑色素瘤扩散的关键。

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