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Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy

BACKGROUND: KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities....

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Autores principales: Saliakoura, Maria, Sebastiano, Matteo Rossi, Nikdima, Ioanna, Pozzato, Chiara, Konstantinidou, Georgia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742413/
https://www.ncbi.nlm.nih.gov/pubmed/34998392
http://dx.doi.org/10.1186/s13046-021-02231-y
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author Saliakoura, Maria
Sebastiano, Matteo Rossi
Nikdima, Ioanna
Pozzato, Chiara
Konstantinidou, Georgia
author_facet Saliakoura, Maria
Sebastiano, Matteo Rossi
Nikdima, Ioanna
Pozzato, Chiara
Konstantinidou, Georgia
author_sort Saliakoura, Maria
collection PubMed
description BACKGROUND: KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer. METHODS: To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the Kras(G12D/+);p53(flox/flox);Pdx1-Cre(ERT2) (KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice. RESULTS: Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment. CONCLUSIONS: Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02231-y.
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spelling pubmed-87424132022-01-10 Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy Saliakoura, Maria Sebastiano, Matteo Rossi Nikdima, Ioanna Pozzato, Chiara Konstantinidou, Georgia J Exp Clin Cancer Res Research BACKGROUND: KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer. METHODS: To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the Kras(G12D/+);p53(flox/flox);Pdx1-Cre(ERT2) (KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice. RESULTS: Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment. CONCLUSIONS: Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02231-y. BioMed Central 2022-01-08 /pmc/articles/PMC8742413/ /pubmed/34998392 http://dx.doi.org/10.1186/s13046-021-02231-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Saliakoura, Maria
Sebastiano, Matteo Rossi
Nikdima, Ioanna
Pozzato, Chiara
Konstantinidou, Georgia
Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy
title Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy
title_full Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy
title_fullStr Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy
title_full_unstemmed Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy
title_short Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy
title_sort restriction of extracellular lipids renders pancreatic cancer dependent on autophagy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742413/
https://www.ncbi.nlm.nih.gov/pubmed/34998392
http://dx.doi.org/10.1186/s13046-021-02231-y
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