Celastrol inhibits angiogenesis and the biological processes of MDA-MB-231 cells via the DEGS1/S1P signaling pathway
Author:
Jia Lulu123, Zhu Shengnan123, Zhu Mingfei123, Nie Rongrong4, Huang Lingyue123, Xu Siyuan123, Luo Yuqin123, Su Huazhen1, Huang Shaoyuan1, Tan Qinyou12356ORCID
Affiliation:
1. Clinical Pharmacy & Pharmacology Research Institute , Affiliated Hospital of Guilin Medical University , 541001 Guilin , Guangxi Province , China 2. Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair , Affiliated Hospital of Guilin Medical University , 541001 Guilin , Guangxi Province , China 3. Laboratory of Hepatobiliary and Pancreatic Surgery , Affiliated Hospital of Guilin Medical University , 541001 Guilin , Guangxi Province , China 4. Rehabilitation Department , Affiliated Hospital of Guilin Medical University , 541001 Guilin , Guangxi Province , China 5. Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases , Affiliated Hospital of Guilin Medical University , 541001 Guilin , Guangxi Province , China 6. China-USA Lipids in Health and Disease Research Center , Guilin Medical University , 541001 Guilin , Guangxi Province , China
Abstract
Abstract
Celastrol (Cel) shows potent antitumor activity in various experimental models. This study examined the relationship between Cel’s antivascular and antitumor effects and sphingolipids. CCK-8 assay, transwell assay, Matrigel, PCR-array/RT-PCR/western blotting/immunohistochemistry assay, ELISA and HE staining were used to detect cell proliferation, migration and invasion, adhesion and angiogenesis, mRNA and protein expression, S1P production and tumor morphology. The results showed that Cel could inhibit proliferation, migration or invasion, adhesion and angiogenesis of human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 cells by downregulating the expression of degenerative spermatocyte homolog 1 (DEGS1). Transfection experiments showed that downregulation of DEGS1 inhibited the above processes and sphingosine-1-phosphate (S1P) production of HUVECs and MDA-MB-231 cells, while upregulation of DEGS1 had the opposite effects. Coculture experiments showed that HUVECs could promote proliferation, migration and invasion of MDA-MB-231 cells through S1P/sphingosine-1-phosphate receptor (S1PR) signaling pathway, while Cel inhibited these processes in MDA-MB-231 cells induced by HUVECs. Animal experiments showed that Cel could inhibit tumor growth in nude mice. Western blotting, immunohistochemistry and ELISA assay showed that Cel downregulated the expression of DEGS1, CD146, S1PR1-3 and S1P production. These data confirm that DEGS1/S1P signaling pathway may be related to the antivascular and antitumor effects of cel.
Funder
Guangxi Municipal Natural Science Foundation Construction Fund of Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases Science and Technology Planned Project in Guilin Guangxi Distinguished Experts Special Fund Medical High Level Talents Training Plan in Guangxi National Natural Science Foundation of China Guilin Medical University
Publisher
Walter de Gruyter GmbH
Subject
Clinical Biochemistry,Molecular Biology,Biochemistry
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