期刊
EMBO JOURNAL
卷 39, 期 1, 页码 -出版社
WILEY
DOI: 10.15252/embj.2019102030
关键词
glioma; lysosome; MALT1; mTOR; protease
资金
- Fondation pour la Recherche Medicale [DEQ20180339184]
- Fondation ARC contre le Cancer [JG PJA20171206146]
- Ligue nationale contre le cancer comites de Loire-Atlantique, Maine et Loire, Vendee, Ille-et-Vilaine
- Region Pays de la Loire et Nantes Metropole under Connect Talent Grant
- SIRIC ILIAD [INCa-DGOS-Inserm_12558]
- Nantes Metropole
- Fondation ARC
- Fondation de France
Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-kappa B activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impairs autophagic flux, and culminates in lysosomal-mediated cell death, concomitantly with mTOR inactivation and dispersion from endo-lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.
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