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DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma.
Wang, Zhen; Tang, Shouyi; Cai, Luyao; Wang, Qing; Pan, Dan; Dong, Yunmei; Zhou, Hao; Li, Jing; Ji, Ning; Zeng, Xin; Zhou, Yu; Shen, Ying-Qiang; Chen, Qianming.
Afiliación
  • Wang Z; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Tang S; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Cai L; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Wang Q; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Pan D; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Dong Y; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Zhou H; Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • Li J; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Ji N; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Zeng X; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
  • Zhou Y; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China. yuzhou1983@scu.edu.cn.
  • Shen YQ; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China. shen@scu.edu.cn.
  • Chen Q; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
Br J Cancer ; 130(11): 1744-1757, 2024 May.
Article en En | MEDLINE | ID: mdl-38582810
ABSTRACT

BACKGROUND:

Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood.

METHODS:

Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects.

RESULTS:

Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis.

CONCLUSION:

Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.
Asunto(s)
Carcinoma de Células Escamosas; Dinaminas; Ferroptosis; Glutamina; Mitocondrias; Dinámicas Mitocondriales; Neoplasias de la Boca; Células Madre Neoplásicas; Ferroptosis/efectos de los fármacos; Humanos; Neoplasias de la Boca/patología; Neoplasias de la Boca/metabolismo; Neoplasias de la Boca/genética; Neoplasias de la Boca/tratamiento farmacológico; Animales; Dinaminas/antagonistas & inhibidores; Dinaminas/genética; Dinaminas/metabolismo; Ratones; Glutamina/metabolismo; Mitocondrias/metabolismo; Mitocondrias/efectos de los fármacos; Células Madre Neoplásicas/metabolismo; Células Madre Neoplásicas/patología; Células Madre Neoplásicas/efectos de los fármacos; Línea Celular Tumoral; Dinámicas Mitocondriales/efectos de los fármacos; Carcinoma de Células Escamosas/patología; Carcinoma de Células Escamosas/metabolismo; Carcinoma de Células Escamosas/genética; Carcinoma de Células Escamosas/tratamiento farmacológico; Ciclo del Ácido Cítrico/efectos de los fármacos; Sistema de Transporte de Aminoácidos ASC/metabolismo; Sistema de Transporte de Aminoácidos ASC/genética; Sistema de Transporte de Aminoácidos ASC/antagonistas & inhibidores; Ácidos Cetoglutáricos/metabolismo; Quinazolinonas/farmacología; Antígenos de Histocompatibilidad Menor/metabolismo; Antígenos de Histocompatibilidad Menor/genética; Piperazinas/farmacología; Carcinoma de Células Escamosas de Cabeza y Cuello/patología; Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo; Carcinoma de Células Escamosas de Cabeza y Cuello/genética; Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Neoplasias de la Boca / Carcinoma de Células Escamosas / Dinaminas / Dinámicas Mitocondriales / Ferroptosis / Glutamina / Mitocondrias Idioma: En Revista: Br J Cancer Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Neoplasias de la Boca / Carcinoma de Células Escamosas / Dinaminas / Dinámicas Mitocondriales / Ferroptosis / Glutamina / Mitocondrias Idioma: En Revista: Br J Cancer Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido