Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation
Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation
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DOI：
10.1158/1541-7786.mcr-20-0637
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发表时间：
2021-05-01
影响因子：
5.2
通讯作者：
Sekido, Yoshitaka
中科院分区：
文献类型：
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作者：
Sato, Tatsuhiro;Mukai, Satomi;Sekido, Yoshitaka
恶性间皮瘤（MM）是一种侵袭性肿瘤，通常在石棉暴露后长时间潜伏后发展。尽管雷帕霉素复合物1（mTORC 1）激活的机制靶点可增强MM细胞生长，但mTORC 1抑制剂依维莫司在MM患者的临床试验中显示出有限的疗效。我们探讨了MM细胞中mTORC 1激活的机制及其对细胞增殖和进展的影响。对来自癌症基因组图谱的87个样本的表达谱的分析显示，40个样本（46%）显示RPTOR（mTORC 1组分）和激活mTORC 1的紧邻上游的基因的表达改变。其中，我们重点研究了RHEB和RHEBL 1，它们编码mTORC 1的直接激活剂。外源性RHEBL 1表达增强MM细胞生长，表明RHEB-mTORC 1信号传导作为促癌级联。我们研究了直接激活RHEB的分子，将SmgGDS鉴定为一种新的RHEB结合蛋白。SmgGDS敲低可降低mTORC 1活化，并抑制mTORC 1活化的MM细胞增殖。有趣的是，SmgGDS显示出与失活的GDP结合的RHEBL 1的高结合亲和力，并且其敲低降低了胞质RHEBL 1而不影响其活化。这些发现表明，SmgGDS保留GDP结合的RHEB在胞质溶胶中，而GTP结合的RHEB定位于细胞内膜上，以促进TORC 1的激活。我们揭示了SmgGDS在RHEB-mTORC 1通路中的新作用及其作为异常mTORC 1激活MM治疗靶点的潜力。
Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on cell proliferation and progression. Analysis of the expression profiles of 87 MMs from The Cancer Genome Atlas revealed that 40 samples (46%) displayed altered expression of RPTOR (mTORC1 component) and genes immediately upstream that activate mTORC1. Among them, we focused on RHEB and RHEBL1, which encode direct activators of mTORC1. Exogenous RHEBL1 expression enhanced MM cell growth, indicating that RHEB-mTORC1 signaling acts as a pro-oncogenic cascade. We investigated molecules that directly activate RHEBs, identifying SmgGDS as a novel RHEB-binding protein. SmgGDS knockdown reduced mTORC1 activation and inhibited the proliferation of MM cells with mTORC1 activation. Interestingly, SmgGDS displayed high binding affinity with inactive GDPbound RHEBL1, and its knockdown reduced cytosolic RHEBL1 without affecting its activation. These findings suggest that SmgGDS retains GDP-bound RHEBs in the cytosol, whereas GTP-bound RHEBs are localized on intracellular membranes to promotemTORC1activation. Werevealed a novel role for SmgGDS in the RHEB-mTORC1 pathway and its potential as a therapeutic target in MM with aberrant mTORC1 activation.