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Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

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

Authors: Irma B. Mitre-Aguilar, Tonatiuh Barrios-Garcia, Victor M. Ruiz-Lopez, Alberto J. Cabrera-Quintero, Nancy R. Mejia-Dominguez, Jose L. Ventura-Gallegos, Daniel Moreno-Mitre, Alejandro Aranda-Gutierrez, Janini Mejia-Rangel, Alma R. Escalona-Guzman, Yanin Chavarri-Guerra, Alfonso Leon-Del-Rio, Alejandro Zentella-Dehesa

Published in: BMC Cancer | Issue 1/2019

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Abstract

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.
Appendix
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Metadata
Title
Glucocorticoid-dependent expression of IAP participates in the protection against TNF-mediated cytotoxicity in MCF7 cells
Authors
Irma B. Mitre-Aguilar
Tonatiuh Barrios-Garcia
Victor M. Ruiz-Lopez
Alberto J. Cabrera-Quintero
Nancy R. Mejia-Dominguez
Jose L. Ventura-Gallegos
Daniel Moreno-Mitre
Alejandro Aranda-Gutierrez
Janini Mejia-Rangel
Alma R. Escalona-Guzman
Yanin Chavarri-Guerra
Alfonso Leon-Del-Rio
Alejandro Zentella-Dehesa
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5563-y

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