Cargando…
MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells
Cushing’s disease (CD) is characterized by cortisol overproduction due to ACTH hypersecretion from a pituitary tumour (PT). With an incidence of approximately 1.2 to 2.4 cases per million per year, CD patients have higher rates of morbidity and mortality than the general population. Surgical managem...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090611/ http://dx.doi.org/10.1210/jendso/bvab048.1108 |
_version_ | 1783687324866969600 |
---|---|
author | Wang, Jason Satou, Motoyasu Tateno, Tae Willette, Sarah Yang, Rui Zhe Kitayoshi, Fumika Teramachi, Mariko Sugimoto, Hiroyuki Chik, Constance L Tateno, Toru |
author_facet | Wang, Jason Satou, Motoyasu Tateno, Tae Willette, Sarah Yang, Rui Zhe Kitayoshi, Fumika Teramachi, Mariko Sugimoto, Hiroyuki Chik, Constance L Tateno, Toru |
author_sort | Wang, Jason |
collection | PubMed |
description | Cushing’s disease (CD) is characterized by cortisol overproduction due to ACTH hypersecretion from a pituitary tumour (PT). With an incidence of approximately 1.2 to 2.4 cases per million per year, CD patients have higher rates of morbidity and mortality than the general population. Surgical management is currently the first therapeutic option. However, remission rates vary between studies, and patients may suffer from complications caused by hormonal abnormalities from remnant PT tissues, the surgery itself, as medical treatment options are limited. Macrophage migratory inhibitory factor (MIF) is a cytokine expressed in various tumors, including ACTH-producing PTs, and has been found to play a crucial role in tumorigenesis. Previous studies demonstrate that MIF regulates cell growth via the signal transducer and activator of transcription 3 (STAT3) pathway, the mammalian target of rapamycin (mTOR) pathway, and autophagy. Together, these indicate MIF as a potential therapeutic target for PTs. However, the role of MIF in ACTH-producing PTs remains unknown. Using mouse ACTH-producing PT cells, AtT-20 cells as a model, we established that MIF overexpression led to increased cell growth. In contrast, pharmacological MIF inhibition by 4-iodo-6-phenylpyrimidine (4-IPP) and (S,R)-3-(4-Hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1) and genetic MIF downregulation by siRNA both suppressed cell viability and induced apoptosis, suggesting an anti-apoptotic role of MIF. Genetic MIF downregulation also increased the expression of apoptosis-inducible genes such as activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and reduced ACTH production. However, pharmacological MIF inhibition had no effect on ACTH production, which suggests that the mechanism of pharmacological MIF inhibition may be different from MIF downregulation. Neither MIF upregulation nor downregulation affected cell signalling pathways such as the STAT3 pathway, the mTOR pathway, or autophagy. Our findings suggest that MIF inhibition can be a viable therapeutic approach for ACTH-producing PTs. |
format | Online Article Text |
id | pubmed-8090611 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-80906112021-05-05 MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells Wang, Jason Satou, Motoyasu Tateno, Tae Willette, Sarah Yang, Rui Zhe Kitayoshi, Fumika Teramachi, Mariko Sugimoto, Hiroyuki Chik, Constance L Tateno, Toru J Endocr Soc Neuroendocrinology and Pituitary Cushing’s disease (CD) is characterized by cortisol overproduction due to ACTH hypersecretion from a pituitary tumour (PT). With an incidence of approximately 1.2 to 2.4 cases per million per year, CD patients have higher rates of morbidity and mortality than the general population. Surgical management is currently the first therapeutic option. However, remission rates vary between studies, and patients may suffer from complications caused by hormonal abnormalities from remnant PT tissues, the surgery itself, as medical treatment options are limited. Macrophage migratory inhibitory factor (MIF) is a cytokine expressed in various tumors, including ACTH-producing PTs, and has been found to play a crucial role in tumorigenesis. Previous studies demonstrate that MIF regulates cell growth via the signal transducer and activator of transcription 3 (STAT3) pathway, the mammalian target of rapamycin (mTOR) pathway, and autophagy. Together, these indicate MIF as a potential therapeutic target for PTs. However, the role of MIF in ACTH-producing PTs remains unknown. Using mouse ACTH-producing PT cells, AtT-20 cells as a model, we established that MIF overexpression led to increased cell growth. In contrast, pharmacological MIF inhibition by 4-iodo-6-phenylpyrimidine (4-IPP) and (S,R)-3-(4-Hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1) and genetic MIF downregulation by siRNA both suppressed cell viability and induced apoptosis, suggesting an anti-apoptotic role of MIF. Genetic MIF downregulation also increased the expression of apoptosis-inducible genes such as activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and reduced ACTH production. However, pharmacological MIF inhibition had no effect on ACTH production, which suggests that the mechanism of pharmacological MIF inhibition may be different from MIF downregulation. Neither MIF upregulation nor downregulation affected cell signalling pathways such as the STAT3 pathway, the mTOR pathway, or autophagy. Our findings suggest that MIF inhibition can be a viable therapeutic approach for ACTH-producing PTs. Oxford University Press 2021-05-03 /pmc/articles/PMC8090611/ http://dx.doi.org/10.1210/jendso/bvab048.1108 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Neuroendocrinology and Pituitary Wang, Jason Satou, Motoyasu Tateno, Tae Willette, Sarah Yang, Rui Zhe Kitayoshi, Fumika Teramachi, Mariko Sugimoto, Hiroyuki Chik, Constance L Tateno, Toru MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells |
title | MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells |
title_full | MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells |
title_fullStr | MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells |
title_full_unstemmed | MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells |
title_short | MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells |
title_sort | mif inhibition suppresses cell viability and induces apoptosis via the atf4-chop pathway in mouse pituitary att-20 cells |
topic | Neuroendocrinology and Pituitary |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090611/ http://dx.doi.org/10.1210/jendso/bvab048.1108 |
work_keys_str_mv | AT wangjason mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT satoumotoyasu mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT tatenotae mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT willettesarah mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT yangruizhe mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT kitayoshifumika mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT teramachimariko mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT sugimotohiroyuki mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT chikconstancel mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells AT tatenotoru mifinhibitionsuppressescellviabilityandinducesapoptosisviatheatf4choppathwayinmousepituitaryatt20cells |