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 GDP-bound 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 promote mTORC1 activation. We revealed a novel role for SmgGDS in the RHEB–mTORC1 pathway and its potential as a therapeutic target in MM with aberrant mTORC1 activation. Implications: Our data showing that SmgGDS regulates RHEB localization to activate mTORC1 indicate that SmgGDS can be used as a new therapeutic target for MM exhibiting mTORC1 activation.

中文翻译：

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沉默 SmgGDS，一种与 RHEB 结合的新型 mTORC1 诱导剂，抑制恶性间皮瘤细胞增殖

恶性间皮瘤 (MM) 是一种侵袭性肿瘤，通常在接触石棉后经过长时间的潜伏期后发展。尽管雷帕霉素复合物 1 (mTORC1) 激活的机制靶点可增强 MM 细胞生长，但 mTORC1 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 mTORC1 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 MM 的表达谱的分析显示，40 个样本（46%）显示 RPTOR（mTORC1 成分）和紧邻激活 mTORC1 的上游基因的表达改变。其中，我们专注于编码 mTORC1 直接激活因子的 RHEB 和 RHEBL1。外源 RHEBL1 表达增强 MM 细胞生长，表明 RHEB-mTORC1 信号传导充当促癌级联反应。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 敲低降低了 mTORC1 的激活并抑制了 mTORC1 激活的 MM 细胞的增殖。有趣的是，SmgGDS 显示出与非活性 GDP 结合的 RHEBL1 的高结合亲和力，并且其敲低减少了细胞溶质 RHEBL1 而不影响其活化。这些发现表明，SmgGDS 在胞质溶胶中保留了与 GDP 结合的 RHEB，而与 GTP 结合的 RHEB 位于细胞内膜上以促进 mTORC1 的激活。我们揭示了 SmgGDS 在 RHEB-mTORC1 通路中的新作用及其作为异常 mTORC1 激活 MM 治疗靶点的潜力。影响：