Ticona-Pérez Fany V, Chen Xi, Pandiella Atanasio, Díaz-Rodríguez Elena
Instituto de Biología Molecular y Celular del Cáncer. CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
CIBERONC, Madrid, Spain.
Cancer Cell Int. 2024 Aug 5;24(1):275. doi: 10.1186/s12935-024-03466-3.
Multiple Myeloma (MM) prognosis has recently improved thanks to the incorporation of new therapies to the clinic. Nonetheless, it is still a non-curable malignancy. Targeting cancer cells with agents inducing cell death has been an appealing alternative investigated over the years, as is the case of TRAIL, an agonist of DR4 and DR5 death receptors. This pathway, involved in apoptosis triggering, has demonstrated efficacy on MM cells. In this research, we have investigated the sensitivity of a panel of MM cells to this agent and generated TRAIL-resistant models by continuous culture of sensitive cells with this peptide. Using genomic and biochemical approaches, the mechanisms underlying resistance were investigated. In TRAIL-resistant cells, a strong reduction in cell-surface receptor levels was detected and impaired the apoptotic machinery to respond to the treatment, enabling cells to efficiently form the Death Inducing Signalling Complex. In addition, an upregulation of the inhibitory protein c-FLIP was detected. Even though the manipulation of these proteins was able to modify cellular responses to TRAIL, it was not complete, pointing to other mechanisms involved in TRAIL resistance.
由于新疗法引入临床，多发性骨髓瘤（MM）的预后近来有所改善。尽管如此，它仍是一种无法治愈的恶性肿瘤。多年来，使用诱导细胞死亡的药物靶向癌细胞一直是一种备受关注的研究方向，TRAIL（DR4和DR5死亡受体的激动剂）就是这样的例子。这条参与触发细胞凋亡的通路已在MM细胞上显示出疗效。在本研究中，我们检测了一组MM细胞对该药物的敏感性，并通过用该肽持续培养敏感细胞建立了TRAIL抗性模型。我们使用基因组学和生物化学方法研究了抗性的潜在机制。在TRAIL抗性细胞中，检测到细胞表面受体水平大幅降低，这损害了细胞凋亡机制对治疗的反应能力，使细胞能够有效地形成死亡诱导信号复合物。此外，还检测到抑制蛋白c-FLIP上调。尽管对这些蛋白的调控能够改变细胞对TRAIL的反应，但并不完全，这表明TRAIL抗性还涉及其他机制。
