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Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids
Fatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated fatty acids (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme active in cancer. Here, we studied how the dynamics between SFAs...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9564215/ https://www.ncbi.nlm.nih.gov/pubmed/36197994 http://dx.doi.org/10.1073/pnas.2203480119 |
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author | Zhao, Guangyuan Tan, Yuying Cardenas, Horacio Vayngart, David Wang, Yinu Huang, Hao Keathley, Russell Wei, Jian-Jun Ferreira, Christina R. Orsulic, Sandra Cheng, Ji-Xin Matei, Daniela |
author_facet | Zhao, Guangyuan Tan, Yuying Cardenas, Horacio Vayngart, David Wang, Yinu Huang, Hao Keathley, Russell Wei, Jian-Jun Ferreira, Christina R. Orsulic, Sandra Cheng, Ji-Xin Matei, Daniela |
author_sort | Zhao, Guangyuan |
collection | PubMed |
description | Fatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated fatty acids (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme active in cancer. Here, we studied how the dynamics between SFAs and UFAs regulated by SCD impacts ovarian cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman scattering (SRS) microscopy. Further, increased levels of SFAs resulting from SCD knockdown triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes. Disorganized ER membrane was visualized by electron microscopy and SRS imaging in ovarian cancer cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and apoptosis could be readily rescued by supplementation with UFAs and reequilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro translated into suppression of intraperitoneal tumor growth in ovarian cancer xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA-enriched diet initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the cancer cell fate under metabolic stress and point to treatment strategies targeting the lipid balance. |
format | Online Article Text |
id | pubmed-9564215 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-95642152023-04-05 Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids Zhao, Guangyuan Tan, Yuying Cardenas, Horacio Vayngart, David Wang, Yinu Huang, Hao Keathley, Russell Wei, Jian-Jun Ferreira, Christina R. Orsulic, Sandra Cheng, Ji-Xin Matei, Daniela Proc Natl Acad Sci U S A Biological Sciences Fatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated fatty acids (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme active in cancer. Here, we studied how the dynamics between SFAs and UFAs regulated by SCD impacts ovarian cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman scattering (SRS) microscopy. Further, increased levels of SFAs resulting from SCD knockdown triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes. Disorganized ER membrane was visualized by electron microscopy and SRS imaging in ovarian cancer cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and apoptosis could be readily rescued by supplementation with UFAs and reequilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro translated into suppression of intraperitoneal tumor growth in ovarian cancer xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA-enriched diet initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the cancer cell fate under metabolic stress and point to treatment strategies targeting the lipid balance. National Academy of Sciences 2022-10-05 2022-10-11 /pmc/articles/PMC9564215/ /pubmed/36197994 http://dx.doi.org/10.1073/pnas.2203480119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Zhao, Guangyuan Tan, Yuying Cardenas, Horacio Vayngart, David Wang, Yinu Huang, Hao Keathley, Russell Wei, Jian-Jun Ferreira, Christina R. Orsulic, Sandra Cheng, Ji-Xin Matei, Daniela Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids |
title | Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids |
title_full | Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids |
title_fullStr | Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids |
title_full_unstemmed | Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids |
title_short | Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids |
title_sort | ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9564215/ https://www.ncbi.nlm.nih.gov/pubmed/36197994 http://dx.doi.org/10.1073/pnas.2203480119 |
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