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Molecular Cancer Research
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Signal Transduction and Functional Imaging

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

Tatsuhiro Sato, Satomi Mukai, Haruna Ikeda, Emi Mishiro-Sato, Ken Akao, Toshiyuki Kobayashi, Okio Hino, Wataru Shimono, Yoshio Shibagaki, Seisuke Hattori and Yoshitaka Sekido
Tatsuhiro Sato
1Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
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Satomi Mukai
1Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
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Haruna Ikeda
1Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
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Emi Mishiro-Sato
2Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
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Ken Akao
1Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
3Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
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Toshiyuki Kobayashi
4Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan.
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  • ORCID record for Toshiyuki Kobayashi
Okio Hino
4Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan.
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Wataru Shimono
5Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan.
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Yoshio Shibagaki
5Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan.
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Seisuke Hattori
5Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan.
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Yoshitaka Sekido
1Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
6Division of Molecular and Cellular Oncology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
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  • For correspondence: ysekido@aichi-cc.jp
DOI: 10.1158/1541-7786.MCR-20-0637
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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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;XX:XX–XX

  • Received July 19, 2020.
  • Revision received December 15, 2020.
  • Accepted February 4, 2021.
  • Published first February 11, 2021.
  • ©2021 American Association for Cancer Research.

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This OnlineFirst version was published on February 26, 2021
doi: 10.1158/1541-7786.MCR-20-0637

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Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation
Tatsuhiro Sato, Satomi Mukai, Haruna Ikeda, Emi Mishiro-Sato, Ken Akao, Toshiyuki Kobayashi, Okio Hino, Wataru Shimono, Yoshio Shibagaki, Seisuke Hattori and Yoshitaka Sekido
Mol Cancer Res February 26 2021 DOI: 10.1158/1541-7786.MCR-20-0637

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Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation
Tatsuhiro Sato, Satomi Mukai, Haruna Ikeda, Emi Mishiro-Sato, Ken Akao, Toshiyuki Kobayashi, Okio Hino, Wataru Shimono, Yoshio Shibagaki, Seisuke Hattori and Yoshitaka Sekido
Mol Cancer Res February 26 2021 DOI: 10.1158/1541-7786.MCR-20-0637
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