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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Ohata H,Shiokawa D,Obata Y,Sato A,Sakai H,Fukami M,Hara W,Taniguchi H,Ono M,Nakagama H,Okamoto Kdoi
10.1016/j.celrep.2019.06.085subject
Has Abstractpub_date
2019-07-30 00:00:00pages
1282-1295.e8issue
5issn
2211-1247pii
S2211-1247(19)30865-4journal_volume
28pub_type
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