Dataset Information

ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.

ABSTRACT: The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyperproliferation, and transformation. Mechanistically, RAC1-driven ROS and NF-κB signaling mediate these processes. Together, these data highlight that ROS production and NF-κB activation triggered by RAC1 are critical events in CRC initiation.

SUBMITTER: Myant KB

PROVIDER: S-EPMC3690525 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.

Myant Kevin B KB Cammareri Patrizia P McGhee Ewan J EJ Ridgway Rachel A RA Huels David J DJ Cordero Julia B JB Schwitalla Sarah S Kalna Gabriela G Ogg Erinn-Lee EL Athineos Dimitris D Timpson Paul P Vidal Marcos M Murray Graeme I GI Greten Florian R FR Anderson Kurt I KI Sansom Owen J OJ

Cell stem cell 20130509 6

The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyper ...[more]

PMID: 23665120

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Project description:BACKGROUND:Lymphotoxin β receptor (LTβR) plays important roles in the development of the immune system and immune response. At the cellular level, ligand-bound LTβR activates the pro-inflammatory NF-κB pathway but the detailed mechanisms regulating its signaling remain unknown. Understanding them is of high importance since LTβR and its ligands are promising therapeutic targets. Here, we studied the consequences of perturbed cellular cholesterol content on LTβR-induced NF-κB signaling. METHODS:To modulate cholesterol availability and/or level in lung carcinoma A549 and H2228, and endothelial HUVEC cells different treatment regimens with filipin, methyl-β-cyclodextrin and simvastatin were applied. LTβR localization was studied by confocal microscopy. The activity of LTβR-induced NF-κB pathway was assessed by measuring the levels of NF-κB pathway inhibitor IκBα and phosphorylation of RelA transcription factor by Western blotting. The NF-κB transcriptional response, production of chemokines and adhesion molecules were examined by qRT-PCR, ELISA, and Western blotting, respectively. Adherence of different types of primary immune cells to epithelial A549 cells and endothelial HUVECs was measured fluorometrically. Interactions of LTβR with its protein partners were investigated by immunoprecipitation. RESULTS:We showed that filipin-mediated sequestration of cholesterol or its depletion from the plasma membrane with methyl-β-cyclodextrin impaired LTβR internalization and potentiated LTβR-dependent activation of the canonical branch of the NF-κB pathway. The latter was manifested by enhanced degradation of IκBα inhibitor, elevated RelA phosphorylation, substantial increase in the expression of NF-κB target genes encoding, among others, cytokines and adhesion molecules known to play important roles in immune response. It was followed by robust secretion of CXCL8 and upregulation of ICAM1, that favored the adhesion of immune cells (NK and T cells, neutrophils) to A549 cells and HUVECs. Mechanistically, we showed that cholesterol depletion stabilized interactions of ligand-stimulated LTβR with modified forms of TRAF2 and NEMO proteins. CONCLUSIONS:Our results showed that the reduction of the plasma membrane content of cholesterol or its sequestration strongly potentiated signaling outcome initiated by LTβR. Thus, drugs modulating cholesterol levels could potentially improve efficacy of LTβR-based therapies. Video abstract.

Dataset Information

ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.

Publications

ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.

Similar Datasets

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