Effects of brusatol on the malignant biological behavior of ovarian cancer cells by regulating SPHK1/S1P/S1PR3 signaling pathway

ZHONG Mingyan; YANG Fan; LI Haizhen; ZHAN Qi; ZHANG Wei

doi:10.6039/j.issn.1001-0408.2024.16.09

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Effects of brusatol on the malignant biological behavior of ovarian cancer cells by regulating SPHK1/S1P/S1PR3 signaling pathway

更新时间：2025-09-23

- Effects of brusatol on the malignant biological behavior of ovarian cancer cells by regulating SPHK1/S1P/S1PR3 signaling pathway
- ZHONGGUO YAOFANG Vol. 35, Issue 16, Pages: 1991-1997(2024)
- 作者机构：
  
  1.九江市妇幼保健院药剂科，江西九江　332000
  2.九江市妇幼保健院妇科，江西九江　332000
  3.九江学院附属医院药剂科，江西九江　332000
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2024.16.09
  CLC： R965;R285.5
- Received：19 February 2024，
  
  Revised：2024-07-23，
  
  Accepted：24 July 2024，
  
  Published：30 August 2024
- 稿件说明：
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钟明艳,杨帆,李海珍,等.鸦胆子苦醇调节SPHK1/S1P/S1PR3信号通路对卵巢癌细胞恶性生物学行为的影响 [J].中国药房,2024,35(16):1991-1997.

ZHONG Mingyan,YANG Fan,LI Haizhen,et al.Effects of brusatol on the malignant biological behavior of ovarian cancer cells by regulating SPHK1/S1P/S1PR3 signaling pathway[J].ZHONGGUO YAOFANG,2024,35(16):1991-1997.
钟明艳,杨帆,李海珍,等.鸦胆子苦醇调节SPHK1/S1P/S1PR3信号通路对卵巢癌细胞恶性生物学行为的影响 [J].中国药房,2024,35(16):1991-1997. DOI： 10.6039/j.issn.1001-0408.2024.16.09.

ZHONG Mingyan,YANG Fan,LI Haizhen,et al.Effects of brusatol on the malignant biological behavior of ovarian cancer cells by regulating SPHK1/S1P/S1PR3 signaling pathway[J].ZHONGGUO YAOFANG,2024,35(16):1991-1997. DOI： 10.6039/j.issn.1001-0408.2024.16.09.

摘要

目的

探讨鸦胆子苦醇调节鞘氨醇激酶1（SPHK1）/鞘氨醇-1-磷酸（S1P）/鞘氨醇-1-磷酸酯受体3（S1PR3）信号通路对卵巢癌细胞恶性生物学行为的影响。

方法

将体外培养的人卵巢癌细胞株SKOV-3随机分为对照组、鸦胆子苦醇组、SPHK1过表达组、鸦胆子苦醇+空载组、鸦胆子苦醇+SPHK1过表达组，检测各组细胞活力、克隆形成率、迁移数、侵袭数、凋亡率以及增殖相关蛋白[骨髓细胞瘤病毒癌基因同源物（C-myc）]、凋亡相关蛋白[B细胞淋巴瘤2（Bcl-2）、Bcl-2相关X蛋白（Bax）]、上皮间质转化（EMT）相关蛋白[上皮钙黏素（E-cadherin）、神经钙黏素（N-cadherin）]及SPHK1、S1P、S1PR3蛋白表达量。采用SKOV-3细胞构建裸鼠移植瘤模型，随机分为对照组、鸦胆子苦醇低剂量组、鸦胆子苦醇中剂量组、鸦胆子苦醇高剂量组、SPHK1过表达组、鸦胆子苦醇高剂量+空载组、鸦胆子苦醇高剂量+SPHK1过表达组，检测各组移植瘤生长情况；随机分为对照组、鸦胆子苦醇组、SPHK1过表达组、鸦胆子苦醇+空载组、鸦胆子苦醇+SPHK1过表达组，检测各组移植瘤组织中增殖、凋亡、EMT及SPHK1/S1P/S1PR3信号通路相关蛋白表达量。

结果

体外实验显示，与对照组相比，鸦胆子苦醇组细胞活力、克隆形成率、迁移数、侵袭数和C-myc、Bcl-2、N-cadherin、SPHK1、S1P、S1PR3蛋白表达量均显著降低（

＜0.05），凋亡率和Bax、E-cadherin蛋白表达量均显著升高（

＜0.05）；过表达SPHK1可减弱鸦胆子苦醇对SKOV-3细胞上述指标的影响。体内实验显示，与对照组相比，鸦胆子苦醇低、中、高剂量组裸鼠干预21 d后的移植瘤体积均显著降低并呈剂量依赖性（

＜0.05）；高剂量鸦胆子苦醇还可显著降低移植瘤组织中C-myc、Bcl-2、N-cadherin、SPHK1、S1P、S1PR3蛋白表达量（

＜0.05），显著升高Bax、E-cadherin蛋白表达量（

＜0.05）；过表达SPHK1可减弱鸦胆子苦醇对移植瘤组织上述指标的影响。

结论

鸦胆子苦醇可通过下调SPHK1/S1P/S1PR3信号通路蛋白表达，进而抑制卵巢癌细胞体外增殖、克隆、EMT、迁移及侵袭并诱导其凋亡，还可抑制卵巢癌细胞在裸鼠体内的生长，最终抑制其恶性生物学行为，对卵巢癌起到显著的抗癌功效。

Abstract

OBJECTIVE

To investigate the effects of brusatol on the malignant biological behavior of ovarian cancer cells by regulating the sphingosine kinase 1 （SPHK1）/sphingosine-1-phosphate （S1P）/sphingosine-1-phosphate receptor 3 （S1PR3） signaling pathway.

METHODS

Human ovarian cancer cell strain SKOV-3 were randomly divided into control group， brusatol group， SPHK1 overexpression group， brusatol+blank load group， brusatol+SPHK1 overexpression group. The cell viability， colony formation rate， the number of migration and invasion， apoptosis rate， the expressions of cell proliferation-related proteins [myelocytomatosis viral oncogene homolog （C-myc）]， apoptosis-related proteins [B-cell lymphoma-2 （Bcl-2）， Bcl-2 associated X protein （Bax）]， epithelial mesenchymal transition （EMT）-related proteins （E-cadherin， N-cadherin） and SPHK1， S1P， S1PR3 proteins were all detected in each group. Transplanted tumor model of nude mice was constructed by using SKOV-3 cells and randomly separated into control group， brusatol low-dose， medium-dose and high-dose groups， SPHK1 overexpression group， high-dose brusatol+blank load group， and high-dose brusatol+SPHK1 overexpression group； the growth of transplanted tumors were detected. The nude mice model of SKOV-3 transplantation tumor was randomly divided into control group， brusatol group， SPHK1 overexpression group， brusatol+blank load group， and brusatol+SPHK1 overexpression group； the proliferation and apoptosis of transplanted tumor tissue， the expressions of EMT-related proteins and SPHK1/S1P/S1PR3 signaling pathway proteins were detected in each group.

RESULTS

Cell experiments

in vitro

had shown that compared with the control group， the cell viability， clone formation rate， migration number， invasion number， protein expressions of C-myc， Bcl-2， N-cadherin， SPHK1， S1P and S1PR3 were decreased significantly in brusatol group （

＜0.05）， while the apoptosis rate， protein expressions of Bax and E-cadherin were increased significantly （

＜0.05）； overexpression of SPHK1 could weaken the effects of brusatol on the above indicators in SKOV-3 cells. Mice experiments

in vivo

had shown that compared with the control group， the transplanted tumor volumes of nude mice in the brusatol low-dose， medium-dose and high-dose groups were decreased significantly in a dose-dependent manner after 21 days of intervention （

＜0.05）. Brusatol of high dose could also significantly reduce the protein expressions of C-myc， Bcl-2， N-cadherin， SPHK1， S1P and S1PR3 in transplanted tumor tissue of nude mice （

＜0.05）， and significantly increase the protein expressions of Bax and E-cadherin （

＜0.05）； overexpression of SPHK1 could weaken the effects of brusatol on the above indicators in transplanted tu

mor tissue of nude mice.

CONCLUSIONS

Brusatol can inhibit the proliferation， cloning， EMT， migration and invasion of ovarian cancer cells， and induce their apoptosis by down-regulating the expression of SPHK1/S1P/S1PR3 signaling pathway. It can also inhibit the growth of ovarian cancer cells in nude mice， ultimately suppressing their malignant biological behavior and exerting significant anti-cancer effects on ovarian cancer.

关键词

Keywords

references

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