Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
Biochem Pharmacol. 2012 Dec 1;84(11):1409-18. doi: 10.1016/j.bcp.2012.08.019. Epub 2012 Sep 1.
Epothilones constitute a novel class of antitubulin agents that are active in patients who relapse after treatment with other chemotherapeutics. This study investigated the molecular mechanisms leading to the onset of epothilone-B (patupilone) resistance in ovarian cancer. Results demonstrated that the Gli family of transcription factors was overexpressed in resistant cells and that treatment with a specific Gli1 inhibitor (GANT58) made cells more susceptible to treatment, partially reversing drug resistance. We also demonstrated that Gli1 knockdown halted growth in resistant cells that were exposed to patupilone, confirming that Gli1 is capable of directly mediating epothilone-B resistance. Another observation from our research was that patupilone-resistant cells produced HGF and acquired characteristics of a mesenchymal phenotype. However, HGF silencing alone was not capable of converting the drug-resistant phenotype to a susceptible one, and in this case we demonstrated that Gli1 overexpression led to an increase in HGF, establishing a functional link between Gli1 and HGF. These results demonstrated that Gli1 played a key role in driving resistance to patupilone, suggesting that the combination of epothilones and Gli1-targeted agents could be exploited to improve outcomes in ovarian cancer patients resistant to standard treatments.
埃坡霉素是一类新型的微管蛋白抑制剂，对其他化疗药物治疗后复发的患者具有活性。本研究探讨了导致卵巢癌患者对埃坡霉素-B（帕他泊汀）产生耐药性的分子机制。结果表明，Gli 家族转录因子在耐药细胞中过度表达，用特异性 Gli1 抑制剂（GANT58）处理可使细胞对治疗更敏感，部分逆转耐药性。我们还证明，在暴露于帕他泊汀的耐药细胞中敲低 Gli1 可阻止其生长，证实 Gli1 能够直接介导埃坡霉素-B 的耐药性。我们研究的另一个观察结果是，帕他泊汀耐药细胞产生 HGF 并获得间充质表型的特征。然而，单独沉默 HGF 并不能将耐药表型转化为敏感表型，在这种情况下，我们证明 Gli1 的过表达导致 HGF 增加，从而在 Gli1 和 HGF 之间建立了功能联系。这些结果表明 Gli1 在驱动对帕他泊汀的耐药性中起关键作用，表明埃坡霉素类药物与Gli1 靶向药物的联合应用可能有助于改善对标准治疗耐药的卵巢癌患者的治疗效果。
