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Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling

OBJECTIVE: Mitochondrial aconitase (ACO2) is an essential enzyme that bridges the TCA cycle and lipid metabolism. However, its role in cancer development remains to be elucidated. The metabolic subtype of colorectal cancer (CRC) was recently established. We investigated ACO2's potential role in...

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Autores principales: You, Xin, Tian, Jingyu, Zhang, Hui, Guo, Yunhua, Yang, Jing, Zhu, Chaofeng, Song, Ming, Wang, Peng, Liu, Zexian, Cancilla, John, Lu, Wenhua, Glorieux, Christophe, Wen, Shijun, Du, Hongli, Huang, Peng, Hu, Yumin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042449/
https://www.ncbi.nlm.nih.gov/pubmed/33676027
http://dx.doi.org/10.1016/j.molmet.2021.101203
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author You, Xin
Tian, Jingyu
Zhang, Hui
Guo, Yunhua
Yang, Jing
Zhu, Chaofeng
Song, Ming
Wang, Peng
Liu, Zexian
Cancilla, John
Lu, Wenhua
Glorieux, Christophe
Wen, Shijun
Du, Hongli
Huang, Peng
Hu, Yumin
author_facet You, Xin
Tian, Jingyu
Zhang, Hui
Guo, Yunhua
Yang, Jing
Zhu, Chaofeng
Song, Ming
Wang, Peng
Liu, Zexian
Cancilla, John
Lu, Wenhua
Glorieux, Christophe
Wen, Shijun
Du, Hongli
Huang, Peng
Hu, Yumin
author_sort You, Xin
collection PubMed
description OBJECTIVE: Mitochondrial aconitase (ACO2) is an essential enzyme that bridges the TCA cycle and lipid metabolism. However, its role in cancer development remains to be elucidated. The metabolic subtype of colorectal cancer (CRC) was recently established. We investigated ACO2's potential role in CRC progression through mediating metabolic alterations. METHODS: We compared the mRNA and protein expression of ACO2 between paired CRC and non-tumor tissues from 353 patients. Correlations between ACO2 levels and clinicopathological features were examined. CRC cell lines with knockdown or overexpression of ACO2 were analyzed for cell proliferation and tumor growth. Metabolomics and stable isotope tracing analyses were used to study the metabolic alterations induced by loss of ACO2. RESULTS: ACO2 decreased in >50% of CRC samples compared with matched non-tumor tissues. Decreased ACO2 levels correlated with advanced disease stage (P < 0.001) and shorter patient survival (P < 0.001). Knockdown of ACO2 in CRC cells promoted cell proliferation and tumor formation, while ectopic expression of ACO2 restrained tumor growth. Specifically, blockade of ACO2 caused a reduction in TCA cycle intermediates and suppression of mitochondrial oxidative phosphorylation, resulting in an increase in glycolysis and elevated citrate flux for fatty acid and lipid synthesis. Increased citrate flux induced upregulation of stearoyl-CoA desaturase (SCD1), which enhanced lipid desaturation in ACO2-deficent cells to favor colorectal cancer growth. Pharmacological inhibition of SCD selectively reduced tumor formation of CRC with ACO2 deficiency. CONCLUSIONS: Our study demonstrated that the rewiring metabolic pathway maintains CRC survival during compromised TCA cycles and characterized the therapeutic vulnerability of lipid desaturation in a meaningful subset of CRC with mitochondrial dysfunction.
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spelling pubmed-80424492021-04-16 Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling You, Xin Tian, Jingyu Zhang, Hui Guo, Yunhua Yang, Jing Zhu, Chaofeng Song, Ming Wang, Peng Liu, Zexian Cancilla, John Lu, Wenhua Glorieux, Christophe Wen, Shijun Du, Hongli Huang, Peng Hu, Yumin Mol Metab Original Article OBJECTIVE: Mitochondrial aconitase (ACO2) is an essential enzyme that bridges the TCA cycle and lipid metabolism. However, its role in cancer development remains to be elucidated. The metabolic subtype of colorectal cancer (CRC) was recently established. We investigated ACO2's potential role in CRC progression through mediating metabolic alterations. METHODS: We compared the mRNA and protein expression of ACO2 between paired CRC and non-tumor tissues from 353 patients. Correlations between ACO2 levels and clinicopathological features were examined. CRC cell lines with knockdown or overexpression of ACO2 were analyzed for cell proliferation and tumor growth. Metabolomics and stable isotope tracing analyses were used to study the metabolic alterations induced by loss of ACO2. RESULTS: ACO2 decreased in >50% of CRC samples compared with matched non-tumor tissues. Decreased ACO2 levels correlated with advanced disease stage (P < 0.001) and shorter patient survival (P < 0.001). Knockdown of ACO2 in CRC cells promoted cell proliferation and tumor formation, while ectopic expression of ACO2 restrained tumor growth. Specifically, blockade of ACO2 caused a reduction in TCA cycle intermediates and suppression of mitochondrial oxidative phosphorylation, resulting in an increase in glycolysis and elevated citrate flux for fatty acid and lipid synthesis. Increased citrate flux induced upregulation of stearoyl-CoA desaturase (SCD1), which enhanced lipid desaturation in ACO2-deficent cells to favor colorectal cancer growth. Pharmacological inhibition of SCD selectively reduced tumor formation of CRC with ACO2 deficiency. CONCLUSIONS: Our study demonstrated that the rewiring metabolic pathway maintains CRC survival during compromised TCA cycles and characterized the therapeutic vulnerability of lipid desaturation in a meaningful subset of CRC with mitochondrial dysfunction. Elsevier 2021-03-03 /pmc/articles/PMC8042449/ /pubmed/33676027 http://dx.doi.org/10.1016/j.molmet.2021.101203 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
You, Xin
Tian, Jingyu
Zhang, Hui
Guo, Yunhua
Yang, Jing
Zhu, Chaofeng
Song, Ming
Wang, Peng
Liu, Zexian
Cancilla, John
Lu, Wenhua
Glorieux, Christophe
Wen, Shijun
Du, Hongli
Huang, Peng
Hu, Yumin
Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling
title Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling
title_full Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling
title_fullStr Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling
title_full_unstemmed Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling
title_short Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling
title_sort loss of mitochondrial aconitase promotes colorectal cancer progression via scd1-mediated lipid remodeling
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042449/
https://www.ncbi.nlm.nih.gov/pubmed/33676027
http://dx.doi.org/10.1016/j.molmet.2021.101203
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