Interplay between Leptin and Stearoyl-CoA Desaturase 1 in Estrogen Receptor-Positive Breast Cancer Cells.

IF 3.6 2区 医学 Q1 PATHOLOGY
Felice Maria Accattatis, Luca Gelsomino, Linda Manna, Piercarlo Del Console, Laura Bianchi, Alfonso Carleo, Rossana De Salvo, Lorenzo Arnaboldi, Ludovica Baù, Alberto Corsini, Adele Elisabetta Leonetti, Rocco Malivindi, Marco Fiorillo, Michael P Lisanti, Cinzia Giordano, Daniela Bonofiglio, Sebastiano Andò, Stefania Catalano, Ines Barone
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Abstract

Obesity, a global health challenge, contributes to various cancers, including breast cancer. Complex metabolic dysregulation marks the development of both breast cancer and obesity. Here, the interplay between the obesity-derived adipokine leptin (LEP) and stearoyl-CoA desaturase 1 (SCD), a critical enzyme in fatty acid (FA) metabolism, was explored. STRING database analysis reported a significant protein-protein interaction between LEP and SCD. Functional processing of the differentially expressed genes in LEP-treated breast cancer cells revealed a critical involvement of SCD in the interactome of differentially expressed gene-coding proteins. Kaplan-Meier analyses linked LEP/SCD expression to poorer recurrence-free survival in patients with estrogen receptor α luminal A-like breast cancer. Functional studies demonstrated that LEP up-regulated SCD expression in luminal A-like breast cancer cells through LEP receptor-mediated signaling and activation of sterol regulatory element-binding-protein-1 (SREBP1), a key transcription factor modulating SCD gene transcription. Lipidomic profiling showed that SCD inhibition using MF-438 reduced LEP-induced FA desaturation, characterized by a shift from saturated to monounsaturated FAs. SCD inhibition also abolished the LEP-mediated mitochondrial respiration and ATP production. Additionally, LEP-induced oncogenic features, including enhanced growth and motility, were counteracted by pharmacologic/genetic SCD blockade, confirming SCD's role in leptin's protumorigenic effects. This study highlights the LEP-SCD axis as a driver of metabolic and functional alterations in estrogen receptor α-positive breast cancer, providing insights into the obesity-breast cancer link and identifying potential therapeutic targets (ie, SCD) to counter obesity-driven breast cancer progression.

雌激素受体阳性乳腺癌细胞中瘦素与硬脂酰辅酶a去饱和酶1的相互作用
肥胖是一个全球性的健康挑战,会导致包括乳腺癌在内的各种癌症。复杂的代谢失调标志着BC和肥胖的发展。本研究探讨了肥胖来源的脂肪因子瘦素(LEP)与脂肪酸(FA)代谢的关键酶硬脂酰辅酶a去饱和酶1 (SCD)之间的相互作用。STRING数据库分析报告了LEP和SCD之间显著的蛋白相互作用。在lep处理的BC细胞中,差异表达基因(deg)的功能加工揭示了SCD在deg编码蛋白的相互作用组中的关键参与。Kaplan-Meier分析将雌激素受体(ER) α腔内a样BC患者的LEP/SCD表达与较差的无复发生存率联系起来。功能研究表明,LEP通过LEP受体介导的信号传导和SREBP1 (Sterol-Regulatory-Element-Binding-Protein-1)的激活,在luminal a -like BC细胞中上调SCD表达,SREBP1是调节SCD基因转录的关键转录因子。脂质组学分析显示,使用MF-438抑制SCD降低了lep诱导的FA去饱和,其特征是从饱和FA转变为单不饱和FA。SCD抑制也消除了lep介导的线粒体呼吸和ATP的产生。此外,lep诱导的致癌特征,包括生长和运动增强,被药理/遗传SCD阻断抵消,证实了SCD在瘦素促肿瘤作用中的作用。本研究强调LEP-SCD轴是er α阳性BC代谢和功能改变的驱动因素,为肥胖-BC之间的联系提供了新的认识,并确定了潜在的治疗靶点(即SCD)来对抗肥胖驱动的BC进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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