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

Hirokazu Ohata; Daisuke Shiokawa; Yuuki Obata; Ai Sato; Hiroaki Sakai; Mayu Fukami; Wakako Hara; Hirokazu Taniguchi; Masaya Ono; Hitoshi Nakagama; Koji Okamoto

doi:10.1016/j.celrep.2019.06.085

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

Cell Rep. 2019 Jul 30;28(5):1282-1295.e8. doi: 10.1016/j.celrep.2019.06.085.

Authors

Affiliations

¹ Division of Cancer Differentiation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
² Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
³ Department of Clinical Proteomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁴ National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁵ Division of Cancer Differentiation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: kojokamo@ncc.go.jp.

PMID: 31365870
DOI: 10.1016/j.celrep.2019.06.085

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.

Keywords: NOX1; ROS; S100A9; cancer stem cells; colon cancer; mTORC1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calgranulin B / genetics
Calgranulin B / metabolism*
Colonic Neoplasms / metabolism*
Colonic Neoplasms / pathology
Humans
Male
Mechanistic Target of Rapamycin Complex 1 / genetics
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mice
NADPH Oxidase 1 / genetics
NADPH Oxidase 1 / metabolism*
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Oxidation-Reduction

Substances

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