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