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肾上腺素通过泛素特异性肽酶 22 介导的脂解环促进乳腺癌转移。

Epinephrine promotes breast cancer metastasis through a ubiquitin-specific peptidase 22-mediated lipolysis circuit.

机构信息

Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China.

Dalian College of Pharmacy, Dalian Medical University, Dalian 116044, China.

出版信息

Sci Adv. 2024 Aug 16;10(33):eado1533. doi: 10.1126/sciadv.ado1533.

DOI:10.1126/sciadv.ado1533
PMID:39151008
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11328899/
Abstract

Chronic stress-induced epinephrine (EPI) accelerates breast cancer progression and metastasis, but the molecular mechanisms remain unclear. Herein, we found a strong positive correlation between circulating EPI levels and the tumoral expression of ubiquitin-specific peptidase 22 (USP22) in patients with breast cancer. USP22 facilitated EPI-induced breast cancer progression and metastasis by enhancing adipose triglyceride lipase (ATGL)-mediated lipolysis. Targeted USP22 deletion decreased ATGL expression and lipolysis, subsequently inhibiting EPI-mediated breast cancer lung metastasis. USP22 acts as a bona fide deubiquitinase for the gene transcription factor FOXO1, and EPI architects a lipolysis signaling pathway to stabilize USP22 through AKT-mediated phosphorylation. Notably, USP22 phosphorylation levels are positively associated with EPI and with downstream pathways involving both FOXO1 and ATGL in breast cancers. Pharmacological USP22 inhibition synergized with β-blockers in treating preclinical xenograft breast cancer models. This study reveals a molecular pathway behind EPI's tumor-promoting effects and provides a strong rationale for combining USP22 inhibition with β-blockers to treat aggressive breast cancer.

摘要

慢性应激诱导的肾上腺素（EPI）会加速乳腺癌的进展和转移，但其中的分子机制尚不清楚。在此，我们发现乳腺癌患者的循环 EPI 水平与泛素特异性肽酶 22（USP22）的肿瘤表达之间存在强烈的正相关。USP22 通过增强脂肪甘油三酯脂肪酶（ATGL）介导的脂肪分解来促进 EPI 诱导的乳腺癌进展和转移。靶向 USP22 缺失会降低 ATGL 的表达和脂肪分解，从而抑制 EPI 介导的乳腺癌肺转移。USP22 作为基因转录因子 FOXO1 的真正去泛素化酶发挥作用，EPI 通过 AKT 介导的磷酸化作用构建脂肪分解信号通路来稳定 USP22。值得注意的是，USP22 的磷酸化水平与 EPI 以及乳腺癌中涉及 FOXO1 和 ATGL 的下游通路呈正相关。USP22 的药理学抑制与β阻断剂联合使用在治疗临床前异种移植乳腺癌模型方面具有协同作用。这项研究揭示了 EPI 促进肿瘤生长的作用背后的分子途径，并为联合使用 USP22 抑制和β阻断剂治疗侵袭性乳腺癌提供了强有力的理论依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c64/11328899/8c84c762d586/sciadv.ado1533-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c64/11328899/bc30299e81b3/sciadv.ado1533-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c64/11328899/8c84c762d586/sciadv.ado1533-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c64/11328899/bc30299e81b3/sciadv.ado1533-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c64/11328899/dd530b2ed805/sciadv.ado1533-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c64/11328899/26612f31e6c5/sciadv.ado1533-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c64/11328899/305bfb3ab2d1/sciadv.ado1533-f4.jpg
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Signal Transduct Target Ther. 2024 Sep 19;9(1):249. doi: 10.1038/s41392-024-01963-5.
β受体阻滞剂可增强蒽环类药物对三阴性乳腺癌转移的控制作用。
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