The Hypoxic Microenvironment Induces Stearoyl-CoA Desaturase-1 Overexpression and Lipidomic Profile Changes in Clear Cell Renal Cell Carcinoma
Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, includin...
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Published in | Cancers Vol. 13; no. 12; p. 2962 |
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Language | English |
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Abstract | Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, including stearoyl-CoA desaturase-1 (SCD-1), which increases the concentration of unsaturated fatty acids in tumor cells. In this work, we studied the expression of SCD-1 in primary ccRCC tumors, as well as in cell lines, to determine its influence on the tumor lipid composition and its role in cell proliferation. The lipidomic analyses of patient tumors showed that oleic acid (18:1n-9) is one of the major fatty acids, and it is particularly abundant in the neutral lipid fraction of the tumor core. Using a ccRCC cell line model and in vitro-generated chemical hypoxia, we show that SCD-1 is highly upregulated (up to 200-fold), and this causes an increase in the cellular level of 18:1n-9, which, in turn, accumulates in the neutral lipid fraction. The pharmacological inhibition of SCD-1 blocks 18:1n-9 synthesis and compromises the proliferation. The addition of exogenous 18:1n-9 to the cells reverses the effects of SCD-1 inhibition on cell proliferation. These data reinforce the role of SCD-1 as a possible therapeutic target. |
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AbstractList | Simple SummaryClear cell renal cell carcinoma (ccRCC) is characterized by a high rate of cell proliferation and an extensive accumulation of lipids. Uncontrolled cell growth usually generates areas of intratumoral hypoxia that define the tumor phenotype. In this work, we show that, under these microenvironmental conditions, stearoyl-CoA desaturase-1 is overexpressed. This enzyme induces changes in the cellular lipidomic profile, increasing the oleic acid levels, a metabolite that is essential for cell proliferation. This work supports the idea of considering stearoyl-CoA desaturase-1 as an exploitable therapeutic target in ccRCC.AbstractClear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, including stearoyl-CoA desaturase-1 (SCD-1), which increases the concentration of unsaturated fatty acids in tumor cells. In this work, we studied the expression of SCD-1 in primary ccRCC tumors, as well as in cell lines, to determine its influence on the tumor lipid composition and its role in cell proliferation. The lipidomic analyses of patient tumors showed that oleic acid (18:1n-9) is one of the major fatty acids, and it is particularly abundant in the neutral lipid fraction of the tumor core. Using a ccRCC cell line model and in vitro-generated chemical hypoxia, we show that SCD-1 is highly upregulated (up to 200-fold), and this causes an increase in the cellular level of 18:1n-9, which, in turn, accumulates in the neutral lipid fraction. The pharmacological inhibition of SCD-1 blocks 18:1n-9 synthesis and compromises the proliferation. The addition of exogenous 18:1n-9 to the cells reverses the effects of SCD-1 inhibition on cell proliferation. These data reinforce the role of SCD-1 as a possible therapeutic target. Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, including stearoyl-CoA desaturase-1 (SCD-1), which increases the concentration of unsaturated fatty acids in tumor cells. In this work, we studied the expression of SCD-1 in primary ccRCC tumors, as well as in cell lines, to determine its influence on the tumor lipid composition and its role in cell proliferation. The lipidomic analyses of patient tumors showed that oleic acid (18:1n-9) is one of the major fatty acids, and it is particularly abundant in the neutral lipid fraction of the tumor core. Using a ccRCC cell line model and in vitro-generated chemical hypoxia, we show that SCD-1 is highly upregulated (up to 200-fold), and this causes an increase in the cellular level of 18:1n-9, which, in turn, accumulates in the neutral lipid fraction. The pharmacological inhibition of SCD-1 blocks 18:1n-9 synthesis and compromises the proliferation. The addition of exogenous 18:1n-9 to the cells reverses the effects of SCD-1 inhibition on cell proliferation. These data reinforce the role of SCD-1 as a possible therapeutic target. |
Author | Aguirre, María V. Melana, Juan Pablo Mignolli, Francesco Stoyanoff, Tania Balboa, María A. Balsinde, Jesús Rodríguez, Juan Pablo |
AuthorAffiliation | 4 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain 1 Laboratorio de Investigaciones Bioquímicas de la Facultad de Medicina (LIBIM), Instituto de Química Básica y Aplicada del Nordeste Argentino (IQUIBA-NEA), Universidad Nacional del Nordeste, Consejo Nacional de Investigaciones Científicas y Técnicas (UNNE-CONICET), Corrientes 3400, Argentina; jpmelana@med.unne.edu.ar (J.P.M.); taniastoyanoff@gmail.com (T.S.); vikyaguirre@yahoo.com (M.V.A.) 2 Instituto de Botánica del Nordeste, Facultad de Ciencias Agrarias (UNNE-CONICET), Universidad Nacional del Nordeste, Corrientes 3400, Argentina; fmignolli80@gmail.com 3 Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, Spain; mbalboa@ibgm.uva.es |
AuthorAffiliation_xml | – name: 2 Instituto de Botánica del Nordeste, Facultad de Ciencias Agrarias (UNNE-CONICET), Universidad Nacional del Nordeste, Corrientes 3400, Argentina; fmignolli80@gmail.com – name: 4 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain – name: 1 Laboratorio de Investigaciones Bioquímicas de la Facultad de Medicina (LIBIM), Instituto de Química Básica y Aplicada del Nordeste Argentino (IQUIBA-NEA), Universidad Nacional del Nordeste, Consejo Nacional de Investigaciones Científicas y Técnicas (UNNE-CONICET), Corrientes 3400, Argentina; jpmelana@med.unne.edu.ar (J.P.M.); taniastoyanoff@gmail.com (T.S.); vikyaguirre@yahoo.com (M.V.A.) – name: 3 Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, Spain; mbalboa@ibgm.uva.es |
Author_xml | – sequence: 1 givenname: Juan Pablo orcidid: 0000-0001-9673-1841 surname: Melana fullname: Melana, Juan Pablo – sequence: 2 givenname: Francesco orcidid: 0000-0003-1346-6734 surname: Mignolli fullname: Mignolli, Francesco – sequence: 3 givenname: Tania surname: Stoyanoff fullname: Stoyanoff, Tania – sequence: 4 givenname: María V. surname: Aguirre fullname: Aguirre, María V. – sequence: 5 givenname: María A. orcidid: 0000-0002-2130-5298 surname: Balboa fullname: Balboa, María A. – sequence: 6 givenname: Jesús orcidid: 0000-0002-4157-6714 surname: Balsinde fullname: Balsinde, Jesús – sequence: 7 givenname: Juan Pablo orcidid: 0000-0002-8713-7178 surname: Rodríguez fullname: Rodríguez, Juan Pablo |
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Snippet | Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation... Simple SummaryClear cell renal cell carcinoma (ccRCC) is characterized by a high rate of cell proliferation and an extensive accumulation of lipids.... |
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SubjectTerms | Apoptosis Cell growth Cell proliferation Chromatography Clear cell-type renal cell carcinoma Desaturase Fatty acids Flow cytometry Hypoxia Kidney cancer Lipid composition Lipid metabolism Lipids Metabolism Metabolites Microenvironments Microscopy Oleic acid Phenotypes Software Stearoyl-CoA desaturase Therapeutic applications Tumor cells Tumors |
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Title | The Hypoxic Microenvironment Induces Stearoyl-CoA Desaturase-1 Overexpression and Lipidomic Profile Changes in Clear Cell Renal Cell Carcinoma |
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