title: Axl molecular targeting counteracts aggressiveness but not platinum-resistance of ovarian carcinoma cells.
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.
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Corno
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gatti
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy.
authors.forename: Noemi
authors.initials: N
authors.lastname: Arrighetti
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy.
authors.forename: Nives
authors.initials: N
authors.lastname: Carenini
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy. Electronic address: paola.perego@istitutotumori.mi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017671:Platinum Compounds / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D017671:Platinum Compounds; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D002945:Cisplatin; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: 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)