Axl molecular targeting counteracts aggressiveness but not platinum-resistance of ovarian carcinoma cells

• Published in: Biochemical pharmacology 2017-07, Vol.136, p.40-50
• Main Authors: Corno, Cristina, Gatti, Laura, Arrighetti, Noemi, Carenini, Nives, Zaffaroni, Nadia, Lanzi, Cinzia, Perego, Paola
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; Axl; Axl Receptor Tyrosine Kinase; Cell Line, Tumor; Cisplatin; Cisplatin - administration & dosage; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Gene Knockdown Techniques - methods; Humans; Molecular Targeted Therapy - methods; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Ovarian carcinoma; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Platinum Compounds - administration & dosage; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Receptor Protein-Tyrosine Kinases - deficiency; Receptor Protein-Tyrosine Kinases - genetics
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2017.04.002

[Display omitted] 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.