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Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis.
Fu, Yu-Hsuan; Tseng, Chi-Yang; Lu, Jeng-Wei; Lu, Wen-Hui; Lan, Pei-Qi; Chen, Chien-Yuan; Ou, Da-Liang; Lin, Liang-In.
Afiliación
  • Fu YH; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 100229, Taiwan.
  • Tseng CY; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 100229, Taiwan.
  • Lu JW; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT-Alliance for Research and Technology, Singapore 138602, Singapore.
  • Lu WH; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 100229, Taiwan.
  • Lan PQ; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 100229, Taiwan.
  • Chen CY; Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan.
  • Ou DL; Department of Oncology, National Taiwan University, Taipei 100025, Taiwan.
  • Lin LI; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 100229, Taiwan.
Biomedicines ; 9(12)2021 Dec 09.
Article en En | MEDLINE | ID: mdl-34944685
Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10-6] and to endoplasmic reticulum stress [p-value = 8.67 × 10-7], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10-8], and responses to a redox state [p-value = 5.80 × 10-5]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10-8] and an ATP metabolic process [p-value = 3.95 × 10-4]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomedicines Año: 2021 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomedicines Año: 2021 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Suiza