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Differential mechanisms involved in RG-7388 and Nutlin-3 induced cell death in SJSA-1 osteosarcoma cells.
Cellular Signalling ( IF 4.8 ) Pub Date : 2020-08-20 , DOI: 10.1016/j.cellsig.2020.109742
Umamaheswari Natarajan 1 , Thiagarajan Venkatesan 1 , Sivanesan Dhandayuthapani 1 , Priya Dondapatti 1 , Appu Rathinavelu 2
Affiliation  

Targeted therapy is becoming the mainstay of cancer treatment due to reduced side effects and enhanced tumor attack. In the last few decades, Murine Double Minute 2 (MDM2) protein has become one of the targets for developing cancer therapies. Blocking MDM2-p53 interaction has long been considered to offer a broad range of advantages during cancer treatment. In this study, we are reporting the differential mechanism of cell death induced by the two small-molecule inhibitors, named RG-7388 and Nutlin-3, that are specific for MDM2 in SJSA-1 Osteosarcoma cells (OS). Mechanistically, RG-7388 was able to enhance the phosphorylation of Mcl-1, which appears to significantly enhance its degradation, thereby relieving the pro-apoptotic protein Bak to execute the apoptosis mechanism. It was noted that the untreated SJSA-1 cells showed an accumulation of Mcl-1 levels, which was decreased following RG-7388 and to a lesser extent by Nutlin-3 and GSK-3β (glycogen synthase kinase 3β) inhibitor treatments. Additionally, we noted that CHIR-99021 (GSK-3β inhibitor) blocked the cytotoxicity exerted by RG-7388 on SJSA-1 cells by decreasing Bak levels. Since Bak is an important pro-apoptotic protein, we hypothesized that phosphorylation of Mcl-1 by GSK-3β could negatively impact the Mcl-1/Bak dimerization and relieve Bak to trigger the loss of mitochondrial membrane potential and thereby initiates apoptosis. We also observed that inhibition of GSK-3β mediated reduction in Bak levels had a protective effect on the mitochondrial membrane integrity, and thus, caused a significant inhibition of the caspase-3 activity and PARP cleavage. Nutlin-3, on the other hand, appears to increase the levels of Bax, leading to the inactivation of Bcl-2, consequently loss of mitochondrial membrane potential and release of Cytochrome c (Cyt c) and elevation of Apaf-1 triggering apoptosis. Thus, to the best of our knowledge, this is the first study that delineates the differences in the molecular mechanism involving two MDM2 inhibitors triggering apoptosis through parallel pathways in SJSA-1 cells. This study further opens new avenues for the use of RG-7388 in treating osteosarcomas that often becomes resistant to chemotherapy due to Bcl-2 overexpression.



中文翻译:

RG-7388 和 Nutlin-3 诱导 SJSA-1 骨肉瘤细胞死亡的差异机制。

由于副作用减少和肿瘤侵袭增强,靶向治疗正成为癌症治疗的主要手段。在过去的几十年中,Murine Double Minute 2 (MDM2) 蛋白已成为开发癌症疗法的目标之一。长期以来,人们一直认为阻断 MDM2-p53 相互作用可在癌症治疗期间提供广泛的优势。在这项研究中,我们报告了由两种小分子抑制剂(RG-7388 和 Nutlin-3)诱导的细胞死亡的不同机制,它们对 SJSA-1 骨肉瘤细胞 (OS) 中的 MDM2 具有特异性。从机制上讲,RG-7388 能够增强 Mcl-1 的磷酸化,这似乎显着增强了其降解,从而减轻了促凋亡蛋白 Bak 以执行凋亡机制。值得注意的是,未经处理的 SJSA-1 细胞显示出 Mcl-1 水平的积累,该水平在 RG-7388 后下降,并在较小程度上通过 Nutlin-3 和 GSK-3β(糖原合酶激酶 3β)抑制剂治疗降低。此外,我们注意到 CHIR-99021(GSK-3β 抑制剂)通过降低 Bak 水平来阻断 RG-7388 对 SJSA-1 细胞的细胞毒性。由于 Bak 是一种重要的促凋亡蛋白,我们假设 GSK-3β 对 Mcl-1 的磷酸化可能会对 Mcl-1/Bak 二聚化产生负面影响并减轻 Bak 以触发线粒体膜电位的丧失,从而引发细胞凋亡。我们还观察到抑制 GSK-3β 介导的 Bak 水平降低对线粒体膜完整性具有保护作用,因此导致 caspase-3 活性和 PARP 裂解的显着抑制。c (Cyt c ) 和 Apaf-1 的升高引发细胞凋亡。因此,据我们所知,这是第一项描述涉及两种 MDM2 抑制剂在 SJSA-1 细胞中通过平行途径触发细胞凋亡的分子机制差异的研究。这项研究进一步为使用 RG-7388 治疗骨肉瘤开辟了新途径,骨肉瘤由于 Bcl-2 过度表达而经常对化疗产生耐药性。

更新日期:2020-08-27
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