Glucocorticoid-dependent expression of IAP participates in the protection against TNF-mediated cytotoxicity in MCF7 cells.

Autor: Mitre-Aguilar IB; Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas (IIBO), Universidad Nacional Autonoma de Mexico (UNAM), 04510 Ciudad de Mexico (CDMX), Mexico, Mexico.; Unidad de Bioquimica, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), 14080, Mexico, CDMX, Mexico., Barrios-Garcia T; Programa de Investigacion en Cancer de Mama, IIBO, UNAM, 04510, Mexico, CDMX, Mexico.; Departamento de Biologia Molecular y Biotecnologia, IIBO, UNAM, 04510, Mexico, CDMX, Mexico., Ruiz-Lopez VM; Departamento de Biologia Molecular, Instituto Nacional de Enfermedades Respiratorias (INER), 14080, Mexico, CDMX, Mexico., Cabrera-Quintero AJ; Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas (IIBO), Universidad Nacional Autonoma de Mexico (UNAM), 04510 Ciudad de Mexico (CDMX), Mexico, Mexico.; Unidad de Bioquimica, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), 14080, Mexico, CDMX, Mexico., Mejia-Dominguez NR; Red de Apoyo a la Investigacion-Coordinacion de la Investigacion Cientifica (RAI-CIC), UNAM, 14080, Mexico, CDMX, Mexico., Ventura-Gallegos JL; Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas (IIBO), Universidad Nacional Autonoma de Mexico (UNAM), 04510 Ciudad de Mexico (CDMX), Mexico, Mexico.; Unidad de Bioquimica, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), 14080, Mexico, CDMX, Mexico., Moreno-Mitre D; Unidad de Bioquimica, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), 14080, Mexico, CDMX, Mexico., Aranda-Gutierrez A; Unidad de Bioquimica, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), 14080, Mexico, CDMX, Mexico., Mejia-Rangel J; Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas (IIBO), Universidad Nacional Autonoma de Mexico (UNAM), 04510 Ciudad de Mexico (CDMX), Mexico, Mexico.; Unidad de Bioquimica, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), 14080, Mexico, CDMX, Mexico., Escalona-Guzman AR; Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas (IIBO), Universidad Nacional Autonoma de Mexico (UNAM), 04510 Ciudad de Mexico (CDMX), Mexico, Mexico.; Unidad de Bioquimica, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), 14080, Mexico, CDMX, Mexico., Chavarri-Guerra Y; Departamento de Hemato-Oncologia, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, 14080, Mexico, CDMX, Mexico., Leon-Del-Rio A; Programa de Investigacion en Cancer de Mama, IIBO, UNAM, 04510, Mexico, CDMX, Mexico.; Departamento de Biologia Molecular y Biotecnologia, IIBO, UNAM, 04510, Mexico, CDMX, Mexico., Zentella-Dehesa A; Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas (IIBO), Universidad Nacional Autonoma de Mexico (UNAM), 04510 Ciudad de Mexico (CDMX), Mexico, Mexico. azentell@iibiomedicas.unam.mx.; Programa de Investigacion en Cancer de Mama, IIBO, UNAM, 04510, Mexico, CDMX, Mexico. azentell@iibiomedicas.unam.mx.; Unidad de Bioquimica, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), 14080, Mexico, CDMX, Mexico. azentell@iibiomedicas.unam.mx.; Centro de Cancer, Centro Medico ABC, 01120, Mexico, CDMX, Mexico. azentell@iibiomedicas.unam.mx.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2019 Apr 15; Vol. 19 (1), pp. 356. Date of Electronic Publication: 2019 Apr 15.
DOI: 10.1186/s12885-019-5563-y
Abstrakt: Background: Glucocorticoid receptor (GR) activation has been associated with breast cancer cell survival in vitro. Glucocorticoid (GC)-dependent protection against tumor necrosis factor (TNF)-induced cell death has been well characterized in MCF7 luminal A breast cancer cells. The GR activates a variety of protective mechanisms, such as inhibitors of apoptosis proteins (IAPs). However, the relative contribution of the GR-dependent expression of IAPs in the protection of cell death has not, to our knowledge, been evaluated.
Methods: MCF7 cells were used for all experiments. GR was activated with cortisol (CORT) or dexamethasone (DEX) and inhibited with mifepristone (RU486). Cell viability was determined in real-time with the xCELLigence™ RTCA System and at specific endpoints using crystal violet stain. The mRNA levels of the eight members of the IAP family were measured by qRT-PCR. The protein levels of GR, PR, ERα, HER2, PARP1, c-IAP1 and XIAP were evaluated by Western blot analysis. The knockdown of c-IAP1 and XIAP was accomplished via transient transfection with specific siRNAs. GR activation was verified by a gene reporter assay. Via the cBioportal interphase we queried the mRNA levels of GR and IAPs in breast cancer tumors.
Results: RU486 significantly inhibited the anti-cytotoxic effect of both GCs. PARP1 processing was diminished in the presence of both GCs. The combined treatments of GCs + TNF increased the relative mRNA levels of Survivin>c-IAP1 > NAIP>Apollon>XIAP>Ts-IAP > ML-IAP > c-IAP2. Additionally, GR mRNA content increased with the combined treatments of GCs + TNF. Sustained levels of the proteins c-IAP1 and XIAP were observed after 48 h of the combined treatments with GCs + TNF. With c-IAP1 and XIAP gene silencing, the GC-mediated protection was diminished. In the breast tumor samples, the GR mRNA was coexpressed with Apollon and XIAP with a Pearson coefficient greater than 0.3.
Conclusions: The effect of GCs against TNF-mediated cytotoxicity involves increased mRNA expression and sustained protein levels of c-IAP1 and XIAP. The antagonist effects of RU486 and the qRT-PCR results also suggest the role of the GR in this process. This finding may have clinical implications because the GR and IAPs are expressed in breast tumor samples.
Databáze: MEDLINE
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