Corno Cristina, Gatti Laura, Arrighetti Noemi, Carenini Nives, Zaffaroni Nadia, Lanzi Cinzia, Perego Paola
Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy.
Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, via Venezian1/via Amadeo 42, 20133 Milan, Italy.
Biochem Pharmacol. 2017 Jul 15;136:40-50. doi: 10.1016/j.bcp.2017.04.002. Epub 2017 Apr 9.
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.
卵巢癌是最常见的妇科癌症，其特点是致死率高，主要原因是诊断晚和治疗失败。基于铂类药物的疗法在该疾病中的疗效受到耐药性的限制，这种现象通常与转移潜能增加有关。由于酪氨酸激酶受体Axl在卵巢癌中可能失调并发挥促转移/抗凋亡作用，本研究的目的是使用多对顺铂敏感和耐药细胞系，研究抑制Axl是否能调节卵巢癌细胞的耐药性和侵袭性特征。我们发现，与亲本IGROV-1细胞相比，铂耐药的IGROV-1/Pt1和IGROV-1/OHP细胞系中Axl的mRNA和蛋白水平升高。IGROV-1/Pt1细胞表现出更强的迁移和侵袭能力。当Axl沉默时，与对照siRNA转染的细胞相比，这些细胞的生长以及侵袭/迁移能力降低，同时p38和STAT3磷酸化水平降低。与此证据一致的是，p38和STAT3的药理学抑制降低了IGROV-1/Pt1的侵袭能力。对Axl的分子抑制并未使IGROV-1/Pt1细胞对顺铂敏感，但增强了IGROV-1/Pt1细胞中ErbB3的激活，并抑制了各种卵巢癌细胞系的克隆形成能力。顺铂与抑制ErbB3的小分子AZD8931联合使用，在IGROV-1/Pt1细胞中产生了协同效应。因此，靶向Axl本身可降低耐药细胞的侵袭能力，但对顺铂敏感则需要同时抑制其他生存途径。
