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NOX1-Dependent mTORC1 Activation via S100A9 Oxidation in Cancer Stem-like Cells Leads to Colon Cancer Progression.

Abstract
Cancer stem cells (CSCs) are associated with the refractory nature of cancer, and elucidating the targetable pathways for CSCs is crucial for devising innovative antitumor therapies. We find that the proliferation of CSC-enriched colon spheroids from clinical specimen is dependent on mTORC1 kinase, which is activated by reactive oxygen species (ROS) produced by NOX1, an NADPH oxidase. In the spheroid-derived xenograft tumors, NOX1 is preferentially expressed in LGR5-positive cells. Dependence on NOX1 expression or mTOR kinase activity is corroborated in the xenograft tumors and mouse colon cancer-derived organoids. NOX1 co-localizes with mTORC1 in VPS41-/VPS39-positive lysosomes, where mTORC1 binds to S100A9, a member of S100 calcium binding proteins, in a NOX1-produced ROS-dependent manner. S100A9 is oxidized by NOX1-produced ROS, which facilitates binding to mTORC1 and its activation. We propose that NOX1-dependent mTORC1 activation via S100A9 oxidation in VPS41-/VPS39-positive lysosomes is crucial for colon CSC proliferation and colon cancer progression.
AuthorsHirokazu Ohata, Daisuke Shiokawa, Yuuki Obata, Ai Sato, Hiroaki Sakai, Mayu Fukami, Wakako Hara, Hirokazu Taniguchi, Masaya Ono, Hitoshi Nakagama, Koji Okamoto
JournalCell reports (Cell Rep) Vol. 28 Issue 5 Pg. 1282-1295.e8 (07 30 2019) ISSN: 2211-1247 [Electronic] United States
PMID31365870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Calgranulin B
  • Neoplasm Proteins
  • S100A9 protein, human
  • S100A9 protein, mouse
  • NADPH Oxidase 1
  • NOX1 protein, human
  • NOX1 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
Topics
  • Animals
  • Calgranulin B (genetics, metabolism)
  • Colonic Neoplasms (metabolism, pathology)
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
  • Mice
  • NADPH Oxidase 1 (genetics, metabolism)
  • Neoplasm Proteins (genetics, metabolism)
  • Neoplastic Stem Cells (metabolism, pathology)
  • Oxidation-Reduction

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