Abstract:
Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies. Rheb activates mTORC1 in the cytosolic surface of lysosomal membranes. Rheb\'s farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDEδ. Recently, the use of PDEδ inhibitors has been proposed as anticancer agents because they interrupted KRas signaling leading to antiproliferative effects in KRas-dependent pancreatic cancer cells. However, the effect of PDEδ inhibition on the Rheb/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDEδ inhibitor, called Deltasonamide 1, in Tsc2-null MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDEδ interaction. Accordingly, we found that Deltasonamide 1 reduces mTORC1 targets activation. In addition, our results showed that Deltasonamide 1 has antiproliferative and cytotoxic effects on Tsc2-null MEFs but has less effect on Tsc2-wild type MEFs viability. This work proposes the pharmacological PDEδ inhibition as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells.
摘要:
Rheb是Ras超家族的一个小的GTPase成员,也是mTORC1的激活剂,mTORC1是细胞代谢的蛋白质复合物主调节因子,增长,和扩散。Rheb/mTORC1通路在增殖性疾病中过度激活,如结节性硬化症综合征和癌症。因此,靶向Rheb依赖性信号是开发新药物治疗的合理策略.Rheb激活溶酶体膜的胞浆表面中的mTORC1。Rheb的法尼化使其锚定在膜上,而其适当的定位取决于异戊二烯结合伴侣PDEδ。最近,已经提出使用PDEδ抑制剂作为抗癌剂,因为它们中断了KRas信号传导,导致KRas依赖性胰腺癌细胞中的抗增殖作用。然而,PDEδ抑制对Rheb/mTORC1途径的影响研究甚少。这里,我们评估了一种新的PDEδ抑制剂的影响,称为Deltasonamide1,在Tsc2空MEF中,Rheb依赖性过度活化的mTORC1细胞系。通过使用酵母双杂交测定法,我们首先验证了Deltasonamide1破坏Rheb-PDEδ相互作用。因此,我们发现Deltasonamide1降低mTORC1靶标的激活。此外,我们的结果表明,Deltasonamide1对Tsc2-nullMEFs具有抗增殖和细胞毒性作用,但对Tsc2-野生型MEFs活力的影响较小.这项工作提出了药理学PDEδ抑制作为靶向结节性硬化症复合体细胞中Rheb/mTORC1异常激活的新方法。