Artículo
Autophagy protects from trastuzumab-induced cytotoxicity in HER2 overexpressing breast tumor spheroids
Rodríguez, Cristina Elisa
; Reidel, Sara I.; Bal, Elisa Dora
; Jasnis, Maria Adela; Fiszman, Gabriel Leon
![Icon](/themes/CONICETDigital/images/conicet.png)
![Icon](/themes/CONICETDigital/images/conicet.png)
Fecha de publicación:
09/2015
Editorial:
Public Library of Science
Revista:
Plos One
ISSN:
1932-6203
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Multicellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.
Palabras clave:
Autophagy
,
Trastuzumab
,
Her2 Breast Cancer
,
Tumor Spheroids
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Colecciones
Articulos(OCA HOUSSAY)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Citación
Rodríguez, Cristina Elisa; Reidel, Sara I.; Bal, Elisa Dora; Jasnis, Maria Adela; Fiszman, Gabriel Leon; Autophagy protects from trastuzumab-induced cytotoxicity in HER2 overexpressing breast tumor spheroids; Public Library of Science; Plos One; 10; 9; 9-2015; 1-16; e0137920
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