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鞘氨醇激酶2/鞘氨醇-1-磷酸通过PAK1/LIMK1/丝切蛋白1信号通路促进三阴性乳腺癌转移。

SphK2/S1P Promotes Metastasis of Triple-Negative Breast Cancer Through the PAK1/LIMK1/Cofilin1 Signaling Pathway.

作者信息

Shi Weiwei, Ma Ding, Cao Yin, Hu Lili, Liu Shuwen, Yan Dongliang, Zhang Shan, Zhang Guang, Wang Zhongxia, Wu Junhua, Jiang Chunping

机构信息

Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.

出版信息

Front Mol Biosci. 2021 Apr 22;8:598218. doi: 10.3389/fmolb.2021.598218. eCollection 2021.

DOI:10.3389/fmolb.2021.598218
PMID:33968977
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8100449/
Abstract

BACKGROUND

Triple-negative breast cancer (TNBC) features a poor prognosis, which is partially attributed to its high metastatic rate. However, there is no effective target for systemic TNBC therapy due to the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors (ER, PR, and HER-2, respectively) in cancer. In the present study, we evaluated the role of sphingosine kinase 2 (SphK2) and its catalyst sphingosine-1-phosphate (S1P) in TNBC metastasis and the effect of the SphK2-specific inhibitor ABC294640 on TNBC metastasis.

METHODS

The function of SphK2 and S1P in TNBC cell metastasis was evaluated using transwell migration and wound-healing assays. The molecular mechanism of SphK2/S1P mediating TNBC metastasis was investigated using Western blot, histological examination, and immunohistochemistry assays. The antitumor activity of ABC294640 was examined in an TNBC lung metastatic model.

RESULTS

Sphingosine kinase 2 promoted TNBC cell migration through the generation of S1P. Targeting SphK2 with ABC294640 inhibited TNBC lung metastasis . p21-activated kinase 1 (PAK1), p-Lin-11/Isl-1/Mec-3 kinase 1 (LIMK1), and Cofilin1 were the downstream signaling molecules of SphK2/S1P. Inhibition of PAK1 suppressed SphK2/S1P-induced TNBC cell migration.

CONCLUSION

Sphingosine kinase 2/sphingosine-1-phosphate promotes TNBC metastasis through the activation of the PAK1/LIMK1/Cofilin1 signaling pathway. ABC294640 inhibits TNBC metastasis and could be developed as a novel agent for the clinical treatment of TNBC.

摘要

背景

三阴性乳腺癌（TNBC）预后较差，部分原因是其高转移率。然而，由于肿瘤中缺乏雌激素、孕激素和人表皮生长因子2受体（分别为ER、PR和HER-2），目前尚无有效的三阴性乳腺癌全身治疗靶点。在本研究中，我们评估了鞘氨醇激酶2（SphK2）及其催化产物鞘氨醇-1-磷酸（S1P）在三阴性乳腺癌转移中的作用，以及SphK2特异性抑制剂ABC294640对三阴性乳腺癌转移的影响。

方法

使用Transwell迁移和伤口愈合试验评估SphK2和S1P在三阴性乳腺癌细胞转移中的作用。通过蛋白质免疫印迹、组织学检查和免疫组织化学试验研究SphK2/S1P介导三阴性乳腺癌转移的分子机制。在三阴性乳腺癌肺转移模型中检测ABC294640的抗肿瘤活性。

结果

鞘氨醇激酶2通过生成S1P促进三阴性乳腺癌细胞迁移。用ABC294640靶向SphK2可抑制三阴性乳腺癌肺转移。p21激活激酶1（PAK1）、p-Lin-11/Isl-1/Mec-3激酶1（LIMK1）和丝切蛋白1是SphK2/S1P的下游信号分子。抑制PAK1可抑制SphK2/S1P诱导的三阴性乳腺癌细胞迁移。

结论

鞘氨醇激酶2/鞘氨醇-1-磷酸通过激活PAK1/LIMK1/丝切蛋白1信号通路促进三阴性乳腺癌转移。ABC294640可抑制三阴性乳腺癌转移，有望开发成为治疗三阴性乳腺癌的新型临床药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/244fa89b776e/fmolb-08-598218-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/320c7fac4bde/fmolb-08-598218-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/21c713970cbb/fmolb-08-598218-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/7f945b606e4b/fmolb-08-598218-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/857f2bbd28da/fmolb-08-598218-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/ea706ff0bf73/fmolb-08-598218-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/bbec4bdc45a3/fmolb-08-598218-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/5a4b29f6657b/fmolb-08-598218-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/244fa89b776e/fmolb-08-598218-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/320c7fac4bde/fmolb-08-598218-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/21c713970cbb/fmolb-08-598218-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/7f945b606e4b/fmolb-08-598218-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/857f2bbd28da/fmolb-08-598218-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/ea706ff0bf73/fmolb-08-598218-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/bbec4bdc45a3/fmolb-08-598218-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/5a4b29f6657b/fmolb-08-598218-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/508a/8100449/244fa89b776e/fmolb-08-598218-g008.jpg

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