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The Differential Effect of Senolytics on SASP Cytokine Secretion and Regulation of EMT by CAFs.
Bogdanova, Daria A; Kolosova, Ekaterina D; Pukhalskaia, Tamara V; Levchuk, Ksenia A; Demidov, Oleg N; Belotserkovskaya, Ekaterina V.
Afiliación
  • Bogdanova DA; Division of Immunobiology and Biomedicine, Sirius University of Science and Technology, Sirius, Krasndarsky Krai, 354340 Sochi, Russia.
  • Kolosova ED; Institute of Cytology RAS, 194064 St. Petersburg, Russia.
  • Pukhalskaia TV; Institute of Cytology RAS, 194064 St. Petersburg, Russia.
  • Levchuk KA; Division of Immunobiology and Biomedicine, Sirius University of Science and Technology, Sirius, Krasndarsky Krai, 354340 Sochi, Russia.
  • Demidov ON; Institute of Cytology RAS, 194064 St. Petersburg, Russia.
  • Belotserkovskaya EV; World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, 197341 St. Petersburg, Russia.
Int J Mol Sci ; 25(7)2024 Apr 04.
Article en En | MEDLINE | ID: mdl-38612842
ABSTRACT
The tumor microenvironment (TME) plays an essential role in tumor progression and in modulating tumor response to anticancer therapy. Cellular senescence leads to a switch in the cell secretome, characterized by the senescence-associated secretory phenotype (SASP), which may regulate tumorigenesis. Senolytic therapy is considered a novel anticancer strategy that eliminates the deleterious effects of senescent cells in the TME. Here, we show that two different types of senolytic drugs, despite efficiently depleting senescent cells, have opposite effects on cancer-associated fibroblasts (CAFs) and their ability to regulate epithelial-mesenchymal transition (EMT). We found that senolytic drugs, navitoclax and the combination of dasatinib/quercetin, reduced the number of spontaneously senescent and TNF-induced senescent CAFs. Despite the depletion of senescent cells, the combination of dasatinib/quercetin versus navitoclax increased the secretion of the SASP pro-inflammatory cytokine IL-6. This differential effect correlated with the promotion of enhanced migration and EMT in MC38 colorectal cancer cells. Our results demonstrate that some senolytics may have side effects unrelated to their senolytic activity and may promote tumorigenesis. We argue for more careful and extensive studies of the effects of senolytics on various aspects of tumor progression and tumor resistance to therapy before the senolytic strategy is implemented in the clinic.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Fibroblastos Asociados al Cáncer / Senoterapéuticos / Compuestos de Anilina Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Rusia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Fibroblastos Asociados al Cáncer / Senoterapéuticos / Compuestos de Anilina Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Rusia Pais de publicación: Suiza