Lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) promote vasculogenesis, angiogenesis, and wound healing by activating a plethora of overlapping signaling pathways that stimulate mitogenesis, cell survival, and migration. As such, maladaptive signaling by LPA and S1P have major effects in increasing tumor progression and producing poor patient outcomes after chemotherapy and radiotherapy. Many signaling actions of S1P and LPA are not redundant; each are vital in normal physiology and their metabolisms differ. In the present work, we studied how LPA signaling impacts S1P metabolism and signaling in MDA-MB-231 and MCF-7 breast cancer cells. LPA increased sphingosine kinase-1 (SphK1) synthesis and rapidly activated cytosolic SphK1 through association with membranes. Blocking phospholipase D activity attenuated the LPA-induced activation of SphK1 and the synthesis of ABCC1 and ABCG2 transporters that secrete S1P from cells. This effect was magnified in doxorubicin-resistant MCF-7 cells. LPA also facilitated S1P signaling by increasing mRNA expression for S1P₁ receptors. Doxorubicin-resistant MCF-7 cells had increased S1P₂ and S1P₃ receptor expression and show increased LPA-induced SphK1 activation, increased expression of ABCC1, ABCG2 and greater S1P secretion. Thus, LPA itself and LPA-induced S1P signaling counteract doxorubicin-induced death of MCF-7 cells. We conclude from the present and previous studies that LPA promotes S1P metabolism and signaling to coordinately increase tumor growth and metastasis and decrease the effectiveness of chemotherapy and radiotherapy for breast cancer treatment.

溶血磷脂酸 (LPA) 和 1-磷酸鞘氨醇 (S1P) 通过激活大量重叠的信号通路来刺激有丝分裂、细胞存活和迁移，从而促进血管生成、血管生成和伤口愈合。因此，LPA 和 S1P 的适应不良信号对加速肿瘤进展以及化疗和放疗后患者预后不良产生重大影响。 S1P和LPA的很多信令动作并不冗余；每种物质在正常生理机能中都至关重要，并且它们的新陈代谢也不同。在目前的工作中，我们研究了 LPA 信号如何影响 MDA-MB-231 和 MCF-7 乳腺癌细胞中的 S1P 代谢和信号。 LPA 增加了鞘氨醇激酶 1 (SphK1) 的合成，并通过与膜的结合快速激活胞质 SphK1。阻断磷脂酶 D 活性可减弱 LPA 诱导的 SphK1 激活以及从细胞中分泌 S1P 的 ABCC1 和 ABCG2 转运蛋白的合成。这种效应在多柔比星耐药的 MCF-7 细胞中被放大。 LPA 还通过增加 S1P ₁受体的 mRNA 表达来促进 S1P 信号传导。多柔比星耐药的 MCF-7 细胞 S1P ₂和 S1P ₃受体表达增加，LPA 诱导的 SphK1 激活增加，ABCC1、ABCG2 表达增加，S1P 分泌增加。因此，LPA 本身和 LPA 诱导的 S1P 信号传导抵消了阿霉素诱导的 MCF-7 细胞死亡。我们从目前和之前的研究得出结论，LPA 促进 S1P 代谢和信号转导，协调增加肿瘤生长和转移，并降低乳腺癌化疗和放疗的有效性。