Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation
| Autor: | Haruna Ikeda, Emi Mishiro-Sato, Seisuke Hattori, Ken Akao, Okio Hino, Yoshitaka Sekido, Wataru Shimono, Toshiyuki Kobayashi, Satomi Mukai, Tatsuhiro Sato, Yoshio Shibagaki |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Mice Nude mTORC1 Mechanistic Target of Rapamycin Complex 1 03 medical and health sciences Mice 0302 clinical medicine Gene silencing Animals Guanine Nucleotide Exchange Factors Humans Inducer Molecular Biology Adaptor Proteins Signal Transducing Cell Proliferation Gene knockdown biology Cell growth Chemistry Mesothelioma Malignant Cytosol Cytoskeletal Proteins 030104 developmental biology HEK293 Cells Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Female Ras Homolog Enriched in Brain Protein biological phenomena cell phenomena and immunity Intracellular RHEB HeLa Cells |
| Zdroj: | Molecular cancer research : MCR. 19(5) |
| ISSN: | 1557-3125 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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