Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, China.
School of Biological Science and Technology, University of Jinan, Jinan, China.
J Cell Physiol. 2019 Jul;234(7):11451-11462. doi: 10.1002/jcp.27802. Epub 2018 Nov 29.
Sphingosylphosphorylcholine (SPC), an important lipid mediator in blood, inhibits the proliferation and migration of various cancer cells. However, its effect as a cell-specific sphingolipid in breast cancer cells is still unknown. Here, we showed that SPC promoted autophagy and apoptosis in triple-negative breast cancer MDA-MB-231 cells. Autophagy worked as a negative regulator of apoptosis-induced by SPC. Mechanistically, SPC mediated apoptosis via activating c-Jun N-terminal kinase (JNK). Meanwhile, p38MAPK (p38) and protein kinase B (PKB or AKT) signaling pathways were also activated to inhibit apoptosis, suggesting that SPC could evoke multiple signaling pathways to modulate cell apoptosis. In addition, the crosstalk between autophagy, p38, AKT and JNK is that autophagy, p38, and AKT attenuated the JNK. AKT and p38 were in the downstream of autophagy, which is autophagy/AKT/p38 signaling evoked by SPC to antagonize JNK signaling and subsequent apoptosis. Although the pathways that antagonize apoptosis were evoked, the cells eventually reached apoptosis by SPC. Therefore, the combination with pharmacological autophagy inhibitors would be a more effective therapeutic strategy for eliminating breast cancer cells by SPC.
鞘氨醇磷胆碱（SPC）是血液中一种重要的脂质介质，能抑制多种癌细胞的增殖和迁移。然而，其作为乳腺癌细胞中特异性鞘脂的作用尚不清楚。本研究表明，SPC 能促进三阴性乳腺癌 MDA-MB-231 细胞自噬和凋亡。自噬作为 SPC 诱导的细胞凋亡的负调控因子起作用。机制上，SPC 通过激活 c-Jun N 端激酶（JNK）介导细胞凋亡。同时，p38MAPK（p38）和蛋白激酶 B（PKB 或 AKT）信号通路也被激活以抑制细胞凋亡，这表明 SPC 可以通过激活多种信号通路来调节细胞凋亡。此外，自噬、p38、AKT 和 JNK 之间的相互作用是自噬、p38 和 AKT 减弱了 JNK。AKT 和 p38 是自噬的下游，SPC 激活自噬/AKT/p38 信号通路拮抗 JNK 信号通路和随后的细胞凋亡。尽管激活了拮抗细胞凋亡的通路，但 SPC 最终仍能诱导细胞凋亡。因此，联合应用药理学自噬抑制剂可能是一种更有效的治疗策略，可通过 SPC 消除乳腺癌细胞。
