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The Hypoxic Microenvironment Induces Stearoyl-CoA Desaturase-1 Overexpression and Lipidomic Profile Changes in Clear Cell Renal Cell Carcinoma

SIMPLE SUMMARY: Clear 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 mic...

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Detalles Bibliográficos
Autores principales: Melana, Juan Pablo, Mignolli, Francesco, Stoyanoff, Tania, Aguirre, María V., Balboa, María A., Balsinde, Jesús, Rodríguez, Juan Pablo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231571/
https://www.ncbi.nlm.nih.gov/pubmed/34199164
http://dx.doi.org/10.3390/cancers13122962
Descripción
Sumario:SIMPLE SUMMARY: Clear 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. 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.