Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research Pub Date : 2025-04-12 DOI:10.1016/j.phrs.2025.107736

Oladimeji Aladelokun , Katherine Benitez , Yuying Wang , Abhishek Jain , Domenica Berardi , Georgio Maroun , Xinyi Shen , Jatin Roper , Joanna Gibson , Kaelyn Sumigray , Sajid A. Khan , Caroline H. Johnson

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引用次数: 0

Abstract

Sex-related differences in asparagine metabolism are associated with cancer prognosis. However, the effect of exogenous asparagine on colorectal cancer (CRC) growth in men and women remains unclear. This study aims to understand the relationship between exogenous asparagine supplementation and 17β-estradiol levels and to elucidate mechanisms underlying sex-dependent signaling during CRC development. We administered asparagine intraperitoneally to tumor-bearing male and female immunodeficient Rag2/Il2RG (R2G2) mice. Asparagine supplementation caused a significant increase in tumor asparagine levels in both the tumor-bearing male and female R2G2 mice but increased serum estradiol levels and suppressed tumor growth in female R2G2 mice only. Additionally, we combined transcriptome, metabolome, and immunochemical analyses, and found that intraperitoneal asparagine treatment induced sex-dependent intra-tumoral metabolic changes to asparagine, aspartate, glutamine and glutamate levels. We observed that in females, exogenous asparagine exerts a negative feed-back effect on de novo asparagine synthesis and is associated with the activation of a sub-population of macrophages that may secrete 17β-estradiol via an aromatase or cytochrome P450 family 19 (CYP19)-dependent mechanism. Conversely, in male mice, asparagine treatment augments tumor growth, and is related to decreased numbers of macrophages, and a reduction in CYP19-mediated 17β-estradiol secretion . Overall, our results reveal a novel and sex-specific role for exogenous asparagine during cancer progression and underscores the importance of understanding mechanisms that control asparagine biosynthesis.

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外源性天冬酰胺对结直肠肿瘤生长、17β-雌二醇水平和芳香化酶的性别特异性影响

天冬酰胺代谢的性别差异与癌症预后有关。然而，外源性天冬酰胺对男性和女性结直肠癌（CRC）生长的影响尚不清楚。本研究旨在了解外源性天冬酰胺补充与17β-雌二醇水平之间的关系，并阐明结直肠癌发展过程中性别依赖信号传导的机制。我们给荷瘤的雄性和雌性免疫缺陷的Rag2/Il2RG （R2G2）小鼠腹腔注射天冬酰胺。在携带肿瘤的雄性和雌性R2G2小鼠中，补充天冬酰胺显著增加了肿瘤的天冬酰胺水平，但仅在雌性R2G2小鼠中增加了血清雌二醇水平并抑制了肿瘤的生长。此外，我们结合转录组学、代谢组学和免疫化学分析，发现腹腔内天冬酰胺治疗诱导了天冬酰胺、天冬氨酸、谷氨酰胺和谷氨酸水平的性别依赖性肿瘤内代谢变化。我们观察到，在雌性中，外源性天冬酰胺对新生天冬酰胺合成产生负反馈效应，并与巨噬细胞亚群的激活有关，这些巨噬细胞可能通过芳香化酶或细胞着色P450家族19 （CYP19）依赖机制分泌17β-雌二醇。相反，在雄性小鼠中，天冬酰胺治疗促进肿瘤生长，并与巨噬细胞数量减少和cyp19介导的17β-雌二醇分泌减少有关。总的来说，我们的研究结果揭示了外源性天冬酰胺在癌症进展过程中的一种新的、性别特异性的作用，并强调了理解控制天冬酰胺生物合成机制的重要性。

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

Pharmacological research 医学-药学

CiteScore

18.70

自引率

3.20%

发文量

491

审稿时长

8 days

期刊介绍： Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.