Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-12

AUTHORS

Cintia Carla da Hora, Kelsey Pinkham, Litia Carvalho, Max Zinter, Elie Tabet, Ichiro Nakano, Bakhos A. Tannous, Christian E. Badr

ABSTRACT

Glioblastoma is an incurable and highly aggressive brain tumor. Understanding therapeutic resistance and survival mechanisms driving this tumor type is key to finding effective therapies. Smac mimetics (SM) emerged as attractive cancer therapeutics particularly for tumor populations that are highly resistant to conventional apoptosis-inducing therapies. We evaluated the therapeutic efficacy of SM on Glioma stem-like cells (GSCs) and showed that this family of compounds stimulates an adaptive response triggered by TNFα. Increased expression of TNFα results in a prolonged and sustained activation of NF-κB and STAT3 signaling thus activating several tumor cell resistance mechanisms in GSCs. We show that STAT3 activation is contingent on EZH2 activation and uncover a synergistic lethality between SM and EZH2 inhibitors. Therapeutic inhibition of EZH2 impaired the viability of SM-treated GSCs. Our study outlines the molecular underpinnings of SM resistance in glioblastoma and provides mechanistic insight to overcome this resistance and increase therapeutic efficacy. More... »

PAGES

72

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41420-019-0155-9

    DOI

    http://dx.doi.org/10.1038/s41420-019-0155-9

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112506568

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30854231


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