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Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma

Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and p...

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Autores principales: Abedin, Yasmin, Gabrilovich, Sofia, Alpert, Emily, Rego, Erica, Begum, Salma, Zhao, Qingshi, Heller, Debra, Einstein, Mark H., Douglas, Nataki C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180633/
https://www.ncbi.nlm.nih.gov/pubmed/35682660
http://dx.doi.org/10.3390/ijms23115980
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author Abedin, Yasmin
Gabrilovich, Sofia
Alpert, Emily
Rego, Erica
Begum, Salma
Zhao, Qingshi
Heller, Debra
Einstein, Mark H.
Douglas, Nataki C.
author_facet Abedin, Yasmin
Gabrilovich, Sofia
Alpert, Emily
Rego, Erica
Begum, Salma
Zhao, Qingshi
Heller, Debra
Einstein, Mark H.
Douglas, Nataki C.
author_sort Abedin, Yasmin
collection PubMed
description Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy.
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spelling pubmed-91806332022-06-10 Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma Abedin, Yasmin Gabrilovich, Sofia Alpert, Emily Rego, Erica Begum, Salma Zhao, Qingshi Heller, Debra Einstein, Mark H. Douglas, Nataki C. Int J Mol Sci Article Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy. MDPI 2022-05-26 /pmc/articles/PMC9180633/ /pubmed/35682660 http://dx.doi.org/10.3390/ijms23115980 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Abedin, Yasmin
Gabrilovich, Sofia
Alpert, Emily
Rego, Erica
Begum, Salma
Zhao, Qingshi
Heller, Debra
Einstein, Mark H.
Douglas, Nataki C.
Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma
title Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma
title_full Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma
title_fullStr Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma
title_full_unstemmed Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma
title_short Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma
title_sort gamma secretase inhibitors as potential therapeutic targets for notch signaling in uterine leiomyosarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180633/
https://www.ncbi.nlm.nih.gov/pubmed/35682660
http://dx.doi.org/10.3390/ijms23115980
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