Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells

Abstract The imipramine ONC201 has antiproliferative effects in several cancer cell types and activates integrated stress response pathway associated with the induction of Damage Inducible Transcript 3 (DDIT3, also known as C/EBP homologous protein or CHOP). We investigated the signaling pathways th...

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Autores principales:	Ashraf Al Madhoun, Dania Haddad, Mustafa Al Tarrah, Sindhu Jacob, Waleed Al-Ali, Rasheeba Nizam, Lavina Miranda, Fatema Al-Rashed, Sardar Sindhu, Rasheed Ahmad, Milad S. Bitar, Fahd Al-Mulla
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/53e9a71543dd4eab8fa13a04b1da0202
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spelling	oai:doaj.org-article:53e9a71543dd4eab8fa13a04b1da02022021-12-02T15:02:40ZMicroarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells10.1038/s41598-021-91092-82045-2322https://doaj.org/article/53e9a71543dd4eab8fa13a04b1da02022021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91092-8https://doaj.org/toc/2045-2322Abstract The imipramine ONC201 has antiproliferative effects in several cancer cell types and activates integrated stress response pathway associated with the induction of Damage Inducible Transcript 3 (DDIT3, also known as C/EBP homologous protein or CHOP). We investigated the signaling pathways through which ONC201/CHOP crosstalk is regulated in ONC201-treated nonmetastatic and metastatic cancer cell lines (Dukes' type B colorectal adenocarcinoma nonmetastatic SW480 and metastatic LS-174T cells, respectively). Cell proliferation and apoptosis were evaluated by MTT assays and flow cytometry, gene expression was assessed by Affymetrix microarray, signaling pathway perturbations were assessed in silico, and key regulatory proteins were validated by Western blotting. Unlike LS-174T cells, SW480 cells were resistant to ONC201 treatment; Gene Ontology analysis of differentially expressed genes showed that cellular responsiveness to ONC201 treatment also differed substantially. In both ONC201-treated cell lines, CHOP expression was upregulated; however, its upstream regulatory mechanisms were perturbed. Although, PERK, ATF6 and IRE1 ER-stress pathways upregulated CHOP in both cell types, the Bak/Bax pathway regulated CHOP only LS-174T cells. Additionally, CHOP RNA splicing profiles varied between cell lines; these were further modified by ONC201 treatment. In conclusion, we delineated the signaling mechanisms by which CHOP expression is regulated in ONC201-treated non-metastatic and metastatic colorectal cell lines. The observed differences could be related to cellular plasticity and metabolic reprogramming, nevertheless, detailed mechanistic studies are required for further validations.Ashraf Al MadhounDania HaddadMustafa Al TarrahSindhu JacobWaleed Al-AliRasheeba NizamLavina MirandaFatema Al-RashedSardar SindhuRasheed AhmadMilad S. BitarFahd Al-MullaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ashraf Al Madhoun Dania Haddad Mustafa Al Tarrah Sindhu Jacob Waleed Al-Ali Rasheeba Nizam Lavina Miranda Fatema Al-Rashed Sardar Sindhu Rasheed Ahmad Milad S. Bitar Fahd Al-Mulla Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells
description	Abstract The imipramine ONC201 has antiproliferative effects in several cancer cell types and activates integrated stress response pathway associated with the induction of Damage Inducible Transcript 3 (DDIT3, also known as C/EBP homologous protein or CHOP). We investigated the signaling pathways through which ONC201/CHOP crosstalk is regulated in ONC201-treated nonmetastatic and metastatic cancer cell lines (Dukes' type B colorectal adenocarcinoma nonmetastatic SW480 and metastatic LS-174T cells, respectively). Cell proliferation and apoptosis were evaluated by MTT assays and flow cytometry, gene expression was assessed by Affymetrix microarray, signaling pathway perturbations were assessed in silico, and key regulatory proteins were validated by Western blotting. Unlike LS-174T cells, SW480 cells were resistant to ONC201 treatment; Gene Ontology analysis of differentially expressed genes showed that cellular responsiveness to ONC201 treatment also differed substantially. In both ONC201-treated cell lines, CHOP expression was upregulated; however, its upstream regulatory mechanisms were perturbed. Although, PERK, ATF6 and IRE1 ER-stress pathways upregulated CHOP in both cell types, the Bak/Bax pathway regulated CHOP only LS-174T cells. Additionally, CHOP RNA splicing profiles varied between cell lines; these were further modified by ONC201 treatment. In conclusion, we delineated the signaling mechanisms by which CHOP expression is regulated in ONC201-treated non-metastatic and metastatic colorectal cell lines. The observed differences could be related to cellular plasticity and metabolic reprogramming, nevertheless, detailed mechanistic studies are required for further validations.
format	article
author	Ashraf Al Madhoun Dania Haddad Mustafa Al Tarrah Sindhu Jacob Waleed Al-Ali Rasheeba Nizam Lavina Miranda Fatema Al-Rashed Sardar Sindhu Rasheed Ahmad Milad S. Bitar Fahd Al-Mulla
author_facet	Ashraf Al Madhoun Dania Haddad Mustafa Al Tarrah Sindhu Jacob Waleed Al-Ali Rasheeba Nizam Lavina Miranda Fatema Al-Rashed Sardar Sindhu Rasheed Ahmad Milad S. Bitar Fahd Al-Mulla
author_sort	Ashraf Al Madhoun
title	Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells
title_short	Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells
title_full	Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells
title_fullStr	Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells
title_full_unstemmed	Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells
title_sort	microarray analysis reveals onc201 mediated differential mechanisms of chop gene regulation in metastatic and nonmetastatic colorectal cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/53e9a71543dd4eab8fa13a04b1da0202
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Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells

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