Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma.

Zhu, Chen; Chen, Xin; Liu, Tian-Qi; Cheng, Lin; Cheng, Wen; Cheng, Peng; Wu, An-Hua

Zhu, Chen; Chen, Xin; Liu, Tian-Qi; Cheng, Lin; Cheng, Wen; Cheng, Peng; Wu, An-Hua.

Afiliação

Zhu C; Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
Chen X; Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
Liu TQ; Institute of Health Sciences, China Medical University, Shenyang, China.
Cheng L; Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
Cheng W; Institute of Health Sciences, China Medical University, Shenyang, China.
Cheng P; Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
Wu AH; Institute of Health Sciences, China Medical University, Shenyang, China.

Nat Commun ; 15(1): 8506, 2024 Oct 01.

Article em En | MEDLINE | ID: mdl-39353936

ABSTRACT

ABSTRACT

Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn't induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.

Assuntos

Neoplasias Encefálicas; Carcinogênese; Glioblastoma; Glicólise; Subunidade alfa do Fator 1 Induzível por Hipóxia; Isocitrato Desidrogenase; beta-N-Acetil-Hexosaminidases; Humanos; Glioblastoma/genética; Glioblastoma/patologia; Glioblastoma/metabolismo; Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo; Subunidade alfa do Fator 1 Induzível por Hipóxia/genética; Isocitrato Desidrogenase/genética; Isocitrato Desidrogenase/metabolismo; Linhagem Celular Tumoral; Animais; Neoplasias Encefálicas/metabolismo; Neoplasias Encefálicas/patologia; Neoplasias Encefálicas/genética; Carcinogênese/genética; Camundongos; beta-N-Acetil-Hexosaminidases/metabolismo; beta-N-Acetil-Hexosaminidases/genética; Microambiente Tumoral/imunologia; Regulação Neoplásica da Expressão Gênica; Macrófagos Associados a Tumor/metabolismo; Macrófagos Associados a Tumor/imunologia; Integrina beta1/metabolismo; Integrina beta1/genética; Glutaratos/metabolismo; Mutação; Proteínas de Sinalização YAP/metabolismo

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Beta-N-Acetil-Hexosaminidases / Neoplasias Encefálicas / Glioblastoma / Subunidade alfa do Fator 1 Induzível por Hipóxia / Carcinogênese / Glicólise / Isocitrato Desidrogenase Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido

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