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Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer

Sulforaphane exerts anti-cancer activity against multiple cancer types. Our objective was to evaluate utility of sulforaphane for endometrial cancer therapy. Sulforaphane reduced viability of endometrial cancer cell lines in association with the G(2)/M cell cycle arrest and cell division cycle prote...

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Autores principales: Rai, Rajani, Gong Essel, Kathleen, Mangiaracina Benbrook, Doris, Garland, Justin, Daniel Zhao, Yan, Chandra, Vishal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281543/
https://www.ncbi.nlm.nih.gov/pubmed/32443471
http://dx.doi.org/10.3390/cancers12051273
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author Rai, Rajani
Gong Essel, Kathleen
Mangiaracina Benbrook, Doris
Garland, Justin
Daniel Zhao, Yan
Chandra, Vishal
author_facet Rai, Rajani
Gong Essel, Kathleen
Mangiaracina Benbrook, Doris
Garland, Justin
Daniel Zhao, Yan
Chandra, Vishal
author_sort Rai, Rajani
collection PubMed
description Sulforaphane exerts anti-cancer activity against multiple cancer types. Our objective was to evaluate utility of sulforaphane for endometrial cancer therapy. Sulforaphane reduced viability of endometrial cancer cell lines in association with the G(2)/M cell cycle arrest and cell division cycle protein 2 (Cdc2) phosphorylation, and intrinsic apoptosis. Inhibition of anchorage-independent growth, invasion, and migration of the cell lines was associated with sulforaphane-induced alterations in epithelial-to-mesenchymal transition (EMT) markers of increased E-cadherin and decreased N-cadherin and vimentin expression. Proteomic analysis identified alterations in AKT, mTOR, and ERK kinases in the networks of sulforaphane effects in the Ishikawa endometrial cancer cell line. Western blots confirmed sulforaphane inhibition of AKT, mTOR, and induction of ERK with alterations in downstream signaling. AKT and mTOR inhibitors reduced endometrial cancer cell line viability and prevented further reduction by sulforaphane. Accumulation of nuclear phosphorylated ERK was associated with reduced sensitivity to the ERK inhibitor and its interference with sulforaphane activity. Sulforaphane induced apoptosis-associated growth inhibition of Ishikawa xenograft tumors to a greater extent than paclitaxel, with no evidence of toxicity. These results verify sulforaphane’s potential as a non-toxic treatment candidate for endometrial cancer and identify AKT, mTOR, and ERK kinases in the mechanism of action with interference in the mechanism by nuclear phosphorylated ERK.
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spelling pubmed-72815432020-06-17 Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer Rai, Rajani Gong Essel, Kathleen Mangiaracina Benbrook, Doris Garland, Justin Daniel Zhao, Yan Chandra, Vishal Cancers (Basel) Article Sulforaphane exerts anti-cancer activity against multiple cancer types. Our objective was to evaluate utility of sulforaphane for endometrial cancer therapy. Sulforaphane reduced viability of endometrial cancer cell lines in association with the G(2)/M cell cycle arrest and cell division cycle protein 2 (Cdc2) phosphorylation, and intrinsic apoptosis. Inhibition of anchorage-independent growth, invasion, and migration of the cell lines was associated with sulforaphane-induced alterations in epithelial-to-mesenchymal transition (EMT) markers of increased E-cadherin and decreased N-cadherin and vimentin expression. Proteomic analysis identified alterations in AKT, mTOR, and ERK kinases in the networks of sulforaphane effects in the Ishikawa endometrial cancer cell line. Western blots confirmed sulforaphane inhibition of AKT, mTOR, and induction of ERK with alterations in downstream signaling. AKT and mTOR inhibitors reduced endometrial cancer cell line viability and prevented further reduction by sulforaphane. Accumulation of nuclear phosphorylated ERK was associated with reduced sensitivity to the ERK inhibitor and its interference with sulforaphane activity. Sulforaphane induced apoptosis-associated growth inhibition of Ishikawa xenograft tumors to a greater extent than paclitaxel, with no evidence of toxicity. These results verify sulforaphane’s potential as a non-toxic treatment candidate for endometrial cancer and identify AKT, mTOR, and ERK kinases in the mechanism of action with interference in the mechanism by nuclear phosphorylated ERK. MDPI 2020-05-18 /pmc/articles/PMC7281543/ /pubmed/32443471 http://dx.doi.org/10.3390/cancers12051273 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rai, Rajani
Gong Essel, Kathleen
Mangiaracina Benbrook, Doris
Garland, Justin
Daniel Zhao, Yan
Chandra, Vishal
Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer
title Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer
title_full Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer
title_fullStr Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer
title_full_unstemmed Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer
title_short Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer
title_sort preclinical efficacy and involvement of akt, mtor, and erk kinases in the mechanism of sulforaphane against endometrial cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281543/
https://www.ncbi.nlm.nih.gov/pubmed/32443471
http://dx.doi.org/10.3390/cancers12051273
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