Dual inhibition of FOXM1 and its compensatory signaling pathway decreased the survival of ovarian cancer cells.
Oncol Rep
; 45(1): 390-400, 2021 01.
Article
em En
| MEDLINE
| ID: mdl-33200225
ABSTRACT
The present study aimed to analyze the compensatory signaling pathways induced by forkhead domain inhibitor6 (FDI6), which is a forkhead box protein M1 (FOXM1) inhibitor, in ovarian cancer cells and evaluate the effectiveness of simultaneous inhibition of FOXM1 and the compensatory signaling pathway in decreasing the survival of ovarian cancer cells. The present study identified the proteins involved in the compensatory mechanism activated by FDI6 in HeyA8 ovarian cancer cells using western blot analysis and a reversephase protein array. In addition, a cell viability assay was performed to determine the effects of FDI6 and the compensatory signaling pathway on cancer cell viability. All experiments were performed in threedimensional cell cultures. The present study observed that FDI6 stimulated the upregulation of NRas, phosphoprotein kinase Cδ (pPKCδ) (S664) and HER3 in HeyA8 cells. Tipifarnib as an NRas inhibitor, rottlerin as a pPKCδ (S664) inhibitor and sapitinib as a HER3 inhibitor were selected. The combination of FDI6 with tipifarnib attenuated the upregulation of NRas induced by FDI6 and the combination of FDI6 with sapitinib also attenuated HER3 downstream signaling pathway in HeyA8 cells, as shown by on western blot analysis. Rottlerin downregulated pPKCδ (S664) by inhibiting the activity of a Srcrelated tyrosine kinase that transfers a phosphate group to PKCδ. Compared with FDI6 alone, the addition of tipifarnib or rottlerin to FDI6 was significantly more effective in reducing the growth of HeyA8 cells. However, the combination of FDI6 and sapitinib did not induce a significant decrease in survival of HeyA8 cells. In conclusion, the addition of tipifarnib or rottlerin to inhibit NRas or pPKCδ (S664), respectively, inhibited the compensatory signaling pathway response induced by FDI6 in HeyA8 cells. These inhibitors increased the efficacy of FDI6, which inhibits FOXM1, in reducing ovarian cancer cell viability.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Piridinas
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Tiofenos
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Proteína Forkhead Box M1
Limite:
Female
/
Humans
Idioma:
En
Revista:
Oncol Rep
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2021
Tipo de documento:
Article