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Autophagy inhibition in breast cancer cells induces ROS-mediated MIF expression and M1 macrophage polarization.
Cotzomi-Ortega, Israel; Nieto-Yañez, Oscar; Juárez-Avelar, Imelda; Rojas-Sanchez, Guadalupe; Montes-Alvarado, José Benito; Reyes-Leyva, Julio; Aguilar-Alonso, Patricia; Rodriguez-Sosa, Miriam; Maycotte, Paola.
Affiliation
  • Cotzomi-Ortega I; Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Km 4.5 Carretera Atlixco-Metepec HGZ5, Puebla 74360, Mexico; Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), Ciudad Universitaria, Puebla 72570, Mexico.
  • Nieto-Yañez O; Unidad de Biomedicina (UBIMED), Facultad de Estudios Superiores Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlanepantla 54090, Mexico.
  • Juárez-Avelar I; Unidad de Biomedicina (UBIMED), Facultad de Estudios Superiores Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlanepantla 54090, Mexico.
  • Rojas-Sanchez G; Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Km 4.5 Carretera Atlixco-Metepec HGZ5, Puebla 74360, Mexico; Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), Ciudad Universitaria, Puebla 72570, Mexico.
  • Montes-Alvarado JB; Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Km 4.5 Carretera Atlixco-Metepec HGZ5, Puebla 74360, Mexico.
  • Reyes-Leyva J; Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Km 4.5 Carretera Atlixco-Metepec HGZ5, Puebla 74360, Mexico.
  • Aguilar-Alonso P; Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), Ciudad Universitaria, Puebla 72570, Mexico.
  • Rodriguez-Sosa M; Unidad de Biomedicina (UBIMED), Facultad de Estudios Superiores Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlanepantla 54090, Mexico. Electronic address: rodriguezm@unam.mx.
  • Maycotte P; Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Km 4.5 Carretera Atlixco-Metepec HGZ5, Puebla 74360, Mexico. Electronic address: paola.maycotte@imss.gob.mx.
Cell Signal ; 86: 110075, 2021 10.
Article in En | MEDLINE | ID: mdl-34229086
ABSTRACT
Autophagy can function as a survival mechanism for cancer cells and therefore, its inhibition is currently being explored as a therapy for different cancer types. For breast cancer, triple negative breast cancer (TNBC) is the subtype most sensitive to the inhibition of autophagy; but its inhibition has also been shown to promote ROS-dependent secretion of macrophage migration inhibitory factor (MIF), a pro-tumorigenic cytokine. In this work, we explore the role of MIF in breast cancer, the mechanism by which autophagy inhibition promotes MIF secretion and its effects on neighboring cancer cell signaling and macrophage polarization. We analyzed MIF mRNA expression levels in tumors from breast cancer patients from different subtypes and found that Luminal B, HER2 and Basal subtypes, which are associated to high proliferation, displayed high MIF levels. However, MIF expression had no prognostic relevance in any breast cancer subtype. In addition, we found that autophagy inhibition in 66cl4 TNBC cells increased intracellular Reactive Oxygen Species (ROS) levels, which increased MIF expression and secretion. MIF secreted from 66cl4 TNBC cells induced the activation of MIF-regulated pathways in syngeneic cell lines, increasing Akt phosphorylation in 4T1 cells and ERK phosphorylation in 67NR cells. Regarding MIF/ chemokine receptors, higher levels of CD74 and CXCR2 were found in TNBC tumor cell lines when compared to non-tumorigenic cells and CXCR7 was elevated in the highly metastatic 4T1 cell line. Finally, secreted MIF from autophagy deficient 66cl4 cells induced macrophage polarization towards the M1 subtype. Together, our results indicate an important role for the inhibition of autophagy in the regulation of ROS-mediated MIF gene expression and secretion, with paracrine effects on cancer cell signaling and pro-inflammatory repercussions in macrophage M1 polarization. This data should be considered when considering the inhibition of autophagy as a therapy for different types of cancer.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Macrophage Migration-Inhibitory Factors / Triple Negative Breast Neoplasms Type of study: Prognostic_studies Limits: Humans Language: En Journal: Cell Signal Year: 2021 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Macrophage Migration-Inhibitory Factors / Triple Negative Breast Neoplasms Type of study: Prognostic_studies Limits: Humans Language: En Journal: Cell Signal Year: 2021 Document type: Article Affiliation country: