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J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33914705

RESUMO

Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, and metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factors hypoxia-inducible factor 1α (HIF-1α) and HIF-2α. Our work demonstrates that HIF-2α is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult, and tumors rapidly acquire resistance to inhibitors of HIF-2α. To overcome this limitation, we performed a small molecule screen to identify HIF-2α-dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell-permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2α-expressing tumor enteroids. Our work demonstrated that HIF-2α integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α upregulated lipid and iron regulatory genes in CRC cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Second, via an iron-dependent, lipid peroxidation-independent pathway, HIF-2α activation potentiated ROS via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2α decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrated a mechanistic vulnerability in cancer cells that were dependent on HIF-2α that can be leveraged for CRC treatment.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Ferro/metabolismo , Proteínas de Neoplasias/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Morte Celular/genética , Hipóxia Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HCT116 , Células HT29 , Humanos , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Oxirredução
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