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Publications

Journal Article Epublish 9 citations

PubMed: 38195762 DOI: 10.1038/s41598-024-51427-7

Mitofusin 1 silencing decreases the senescent associated secretory phenotype, promotes immune cell recruitment and delays melanoma tumor growth after chemotherapy.

Sci Rep 14(1):909

Authors: Doménica Tarallo, Jennyfer Martínez, Alejandro Leyva, Amy Mónaco, Carolina Perroni, Marcos Tassano, Juan Pablo Gambini, Mónica Cappetta, Rosario Durán, María Moreno, Celia Quijano

Affiliations

  • Departamento de Bioquímica, Facultad de Medicina, and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.
  • Institut Pasteur de Montevideo and Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay.
  • Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
  • Area Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
  • Centro Uruguayo de Imagenología Molecular (CUDIM) and Centro de Medicina Nuclear (CMN), Hospital de Clínicas Dr. Manuel Quintela, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
  • Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
  • Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
  • Departamento de Bioquímica, Facultad de Medicina, and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.

Abstract

Cellular senescence is a therapy endpoint in melanoma, and the senescence-associated secretory phenotype (SASP) can affect tumor growth and microenvironment, influencing treatment outcomes. Metabolic interventions can modulate the SASP, and mitochondrial energy metabolism supports resistance to therapy in melanoma. In a previous report we showed that senescence, induced by the DNA methylating agent temozolomide, increased the level of fusion proteins mitofusin 1 and 2 in melanoma, and silencing Mfn1 or Mfn2 expression reduced interleukin-6 secretion by senescent cells. Here we expanded these observations evaluating the secretome of senescent melanoma cells using shotgun proteomics, and explored the impact of silencing Mfn1 on the SASP. A significant increase in proteins reported to reduce the immune response towards the tumor was found in the media of senescent cells. The secretion of several of these immunomodulatory proteins was affected by Mfn1 silencing, among them was galectin-9. In agreement, tumors lacking mitofusin 1 responded better to treatment with the methylating agent dacarbazine, tumor size was reduced and a higher immune cell infiltration was detected in the tumor. Our results highlight mitochondrial dynamic proteins as potential pharmacological targets to modulate the SASP in the context of melanoma treatment.

MeSH

Growth, Natural Science Disciplines, Melanoma, Drug Therapy, Cellular Senescence, Cells, Therapeutics, Neoplasms, Interleukin-6, Phenotype, Chemotherapy

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