Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation

Abstract

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.

Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma and implications for immunotherapy

“…NOTCH signaling facilitates immune escape by up-regulating PD-L1 and is associated with the expansion of exhausted CD8+ T cells (76). Expression profiles of malignant mesotheliomas revealed that 46% displayed altered expression of RPTOR (mTORC1 component) that activates the mechanistic target of rapamycin complex 1 (mTORC1) to enhance MM cell growth (77) suggesting the worse outcome of nuclear DAMPs subtype. On the other hand, studies have demonstrated the potential role of IL-8 as a driver of resistance to ICIs and that IL-8 has an essential role in reinforcing the immunosuppressive microenvironment and triggering EMT by determining the types and quantity of myeloid cells infiltrating tumors (78,79).…”

Machine learning and bioinformatics-based insights into the potential targets of saponins in Paris polyphylla smith against non-small cell lung cancer

“…In breast cancer cells MCF7, scholars found that overexpression of RhebL1 increased the expression of mesenchymal markers and decreased the expression of E-cadherin in MCF7 and that downregulation of this gene significantly reduced the migration and invasion of MCF7 cells ( Kim and Lee, 2018 ). Several studies also found that high expression of exogenous RHEBL1 promoted the growth of malignant mesothelioma cells and probed that RHEB-mTORC1 signaling has a pro-carcinogenic effect ( Bonneau and Parmar, 2012 ; Sato et al, 2021 ). In terms of RNPC3, little is known about the role of RNPC3 protein in human cancers, and some studies have shown that genes including RNPC3 can be used as diagnostic genes for lung adenocarcinoma ( Li et al, 2020 ).…”