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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;R285.5Published：30 August 2024，
Received：19 February 2024，
Revised：23 July 2024，
- 稿件说明：
扫 描 看 全 文
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 Δ[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 Δ[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
2
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
2
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
2
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（
P
＜0.05），凋亡率和Bax、E-cadherin蛋白表达量均显著升高（
P
＜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（
P
＜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（
P
＜0.05），显著升高Bax、E-cadherin蛋白表达量（
P
＜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
2
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
2
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
2
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
2
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 （
P
＜0.05）， while the apoptosis rate， protein expressions of Bax and E-cadherin were increased significantly （
P
＜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 （
P
＜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 （
P
＜0.05）， and significantly increase the protein expressions of Bax and E-cadherin （
P
＜0.05）； overexpression of SPHK1 could weaken the effects of brusatol on the above indicators in transplanted tu
mor tissue of nude mice.
CONCLUSIONS
2
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
鸦胆子苦醇SPHK1/S1P/S1PR3信号通路卵巢癌恶性生物学行为
Keywords
SPHK1/S1P/S1PR3 signaling pathwayovarian cancermalignant biological behavior
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