164P Effect of ELOVL5 expression on breast cancer development

Kieu, Trinh-Le-Vi; Pierre, Lenz Sacha Christyl; Perrey, Stéphane; Dérangère, Valentin; Truntzer, Caroline; Jalil, Abdelali; Agathe, Dumont; Masson, Damien; Thomas, C.; Ghiringhelli, F.; Rialland, Mickaël

doi:10.1016/j.annonc.2021.08.445

Cited by 2 publications

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“…It is known that its expression in breast cancer cells is elevated and that it directly affects the lipid composition in serum (Tomida et al, 2021). Moreover, the complete knockout of ELOVL5 in the mouse breast carcinoma model led to a delay in tumor development and a decrease in tumor growth (Kieu et al, 2021). At the same time, the data on the impact of the IGFBP6 gene on the lipid metabolism are limited.…”

Section: Discussionmentioning

confidence: 99%

ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis

Никулин

Razumovskaya

Poloznikov

et al. 2023

Front. Mol. Biosci.

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Introduction: Relapse of breast cancer is one of the key obstacles to successful treatment. Previously we have shown that low expression of ELOVL5 and IGFBP6 genes in breast cancer tissue corresponded to poor prognosis. ELOVL5 participates directly in the elongation of polyunsaturated fatty acids (PUFAs) that are considered to play an important role in cancer cell metabolism. Thus, in this work we studied the changes in lipid metabolism in breast cancer cells with reduced expression of either ELOVL5 or IGFBP6 gene.Methods: MDA-MB-231 cells with a stable knockdown of either ELOVL5 or IGFBP6 gene were used in this study. Transcriptomic and proteomic analysis as well as RT-PCR were utilized to assess gene expression. Content of individual fatty acids in the cells was measured with HPLC-MS. HPLC was used for analysis of the kinetics of PUFAs uptake. Cell viability was measured with MTS assay. Flow cytometry was used to measure activation of apoptosis. Fluorescent microscopy was utilized to assess accumulation of ROS and formation of lipid droplets. Glutathione peroxidase activity was measured with a colorimetric assay.Results: We found that the knockdown of IGFBP6 gene led to significant changes in the profile of fatty acids in the cells and in the expression of many genes associated with lipid metabolism. As some PUFAs are known to inhibit proliferation and cause death of cancer cells, we also tested the response of the cells to single PUFAs and to combinations of docosahexaenoic acid (DHA, a n-3 PUFA) with standard chemotherapeutic drugs. Our data suggest that external PUFAs cause cell death by activation of ferroptosis, an iron-dependent mechanism of cell death with excessive lipid peroxidation. Moreover, both knockdowns increased cells’ sensitivity to ferroptosis, probably due to a significant decrease in the activity of the antioxidant enzyme GPX4. Addition of DHA to commonly used chemotherapeutic drugs enhanced their effect significantly, especially for the cells with low expression of IGFBP6 gene.Discussion: The results of this study suggest that addition of PUFAs to the treatment regimen for the patients with low expression of IGFBP6 and ELOVL5 genes can be potentially beneficial and is worth testing in a clinically relevant setting.

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Section: Discussionmentioning

confidence: 99%

ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis

Никулин

Razumovskaya

Poloznikov

et al. 2023

Front. Mol. Biosci.

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“…Furthermore, ELOVL5 is highly expressed in the central nervous system and mutations in the gene were found to be the cause of spinocerebellar ataxia type 38 (SCA38), a rare autosomal neurological disease characterized by gait abnormality, dysarthria, dysphagia, hyposmia, and peripheral neuropathy (Balbo et al, 2021). While reduction in ELOVL5 expression has been linked to worsened prognosis in breast estrogen receptor-positive cancer patients (Kieu et al, 2022), its role in behavior regulation is still unclear. The observed increased expression of ELOVL5 and FADS2 in Sub mice, together with the elevation of the parental DA and EPA levels, as well as with DEA and related metabolites, suggest that the signaling pathways mediated by these molecules are of importance for social behavior and personality manifestations.…”

Section: Discussionmentioning

confidence: 99%

Endocannabinoid basis of personality—Insights from animal model of social behavior

Kogan,

Begmatova,

Vinnikova

et al. 2023

Front. Pharmacol.

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Rationale: The endocannabinoid system is known to be involved in learning, memory, emotional processing and regulation of personality patterns. Here we assessed the endocannabinoid profile in the brains of mice with strong characteristics of social dominance and submissiveness.Methods: A lipidomics approach was employed to assess the endocannabinoidome in the brains of Dominant (Dom) and Submissive (Sub) mice. The endocannabinoid showing the greatest difference in concentration in the brain between the groups, docosatetraenoyl ethanolamine (DEA), was synthesized, and its effects on the physiological and behavioral responses of Dom and Sub mice were evaluated. mRNA expression of the endocannabinoid receptors and enzymes involved in PUFA biosynthesis was assessed using qRT-PCR.Results: Targeted LC/MS analysis revealed that long-chain polyunsaturated ethanolamides including arachidonoyl ethanolamide (AEA), DEA, docosatrienoyl ethanolamide (DTEA), eicosatrienoyl ethanolamide (ETEA), eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) were higher in the Sub compared with the Dom mice. Untargeted LC/MS analysis showed that the parent fatty acids, docosatetraenoic (DA) and eicosapentaenoic (EPA), were higher in Sub vs. Dom. Gene expression analysis revealed increased mRNA expression of genes encoding the desaturase FADS2 and the elongase ELOVL5 in Sub mice compared with Dom mice. Acute DEA administration at the dose of 15 mg/kg produced antinociceptive and locomotion-inducing effects in Sub mice, but not in Dom mice. Subchronic treatment with DEA at the dose of 5 mg/kg augmented dominant behavior in wild-type ICR and Dom mice but not in Sub mice.Conclusion: This study suggests that the endocannabinoid system may play a role in the regulation of dominance and submissiveness, functional elements of social behavior and personality. While currently we have only scratched the surface, understanding the role of the endocannabinoid system in personality may help in revealing the mechanisms underlying the etiopathology of psychiatric disorders.

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164P Effect of ELOVL5 expression on breast cancer development

Cited by 2 publications

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ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis

ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis

Endocannabinoid basis of personality—Insights from animal model of social behavior

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