Axl molecular targeting counteracts aggressiveness but not platinum-resistance of ovarian carcinoma cells.
Biochem Pharmacol
; 136: 40-50, 2017 07 15.
Article
em En
| MEDLINE
| ID: mdl-28404378
ABSTRACT
Ovarian carcinoma, the most common gynaecological cancer, is characterized by high lethality mainly due to late diagnosis and treatment failure. The efficacy of platinum drug-based therapy in the disease is limited by the occurrence of drug resistance, a phenomenon often associated with increased metastatic potential. Because the Tyr-kinase receptor Axl can be deregulated in ovarian carcinoma and plays a pro-metastatic/anti-apoptotic role, the aim of this study was to examine if Axl inhibition modulates drug resistance and aggressive features of ovarian carcinoma cells, using various pairs of cisplatin-sensitive and -resistant cell lines. We found that mRNA and protein levels of Axl were increased in the platinum-resistant IGROV-1/Pt1 and IGROV-1/OHP cell lines compared to the parental IGROV-1 cells. IGROV-1/Pt1 cells displayed increased migratory and invasive capabilities. When Axl was silenced, these cells exhibited reduced growth and invasive/migratory capabilities compared to control siRNA-transfected cells, associated with decreased p38 and STAT3 phosphorylation. In keeping with this evidence, pharmacological inhibition of p38 and STAT3 decreased IGROV-1/Pt1 invasive capability. Molecular inhibition of Axl did not sensitize IGROV-1/Pt1 cells to cisplatin, but enhanced ErbB3 activation in IGROV-1/Pt1 cells and suppressed the clonogenic capability of various ovarian carcinoma cell lines. The combination of cisplatin and AZD8931, a small molecule which inhibits ErbB3, produced a synergistic effect in IGROV-1/Pt1 cells. Thus, Axl targeting per se reduces invasive capability of drug-resistant cells, but sensitization to cisplatin requires the concomitant inhibition of additional survival pathways.
Palavras-chave
AZD8931 (PubChem CID: 11488320); Axl; CI-1040 (PubChem CID: 6918454); Cisplatin; Cisplatin (PubChem CID: 2767); Drug resistance; Gefitinib (PubChem CID: 123631); Ovarian carcinoma; R428 (PubChem CID: 46215462); SB203580 (PubChem CID: 176155); Stattic (PubChem CID: 2779853); Taxol (PubChem CID: 36314)
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Limite:
Female
/
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article