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微小肽hSPAR通过TRIM21-P27KIP1-mTOR轴调节谷氨酰胺水平并抑制乳腺肿瘤生长。

Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis.

作者信息

Huang Yan, Lu Hua, Liu Yao, Wang Jiabei, Xia Qingan, Shi Xiangmin, Jin Yan, Liang Xiaolin, Wang Wei, Ma Xiaopeng, Wang Yangyi, Gong Meng, Li Canjun, Cang Chunlei, Cui Qinghua, Chen Ceshi, Shen Tao, Liu Lianxin, Wang Xiangting

机构信息

Department of Geriatrics, Gerontology Institute of Anhui Province, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, China.

出版信息

EMBO J. 2025 Mar;44(5):1414-1441. doi: 10.1038/s44318-024-00359-z. Epub 2025 Jan 28.

DOI:10.1038/s44318-024-00359-z
PMID:39875724
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11876615/
Abstract

mTOR plays a pivotal role in cancer growth control upon amino acid response. Recently, CDK inhibitor P27KIP1 has been reported as a noncanonical inhibitor of mTOR signaling in MEFs, via unclear mechanisms. Here, we find that P27KIP1 degradation via E3 ligase TRIM21 is inhibited by human micropeptide hSPAR through its C-terminus (hSPAR-C), causing P27KIP1's cytoplasmic accumulation in breast cancer cells. Furthermore, hSPAR/hSPAR-C also serves as an inhibitor of glutamine transporter SLC38A2 expression and thereby decreases the cellular glutamine levels specifically in cancer cells. The resultant glutamine deprivation sequentially triggers translocation of cytoplasmic P27KIP1 to lysosomes, where P27KIP1 disrupts the Ragulator complex and suppresses mTORC1 assembly. Administration of hSPAR or hSPAR-C significantly impedes breast cancer cell proliferation and tumor growth in xenograft models. These findings define hSPAR as an intrinsic control factor for cellular glutamine levels and as a novel tumor suppressor inhibiting mTORC1 assembly.

摘要

在氨基酸应答过程中，mTOR在癌症生长控制中发挥着关键作用。最近，有报道称细胞周期蛋白依赖性激酶抑制剂P27KIP1是小鼠胚胎成纤维细胞中mTOR信号通路的非典型抑制剂，但其作用机制尚不清楚。在此，我们发现人微小肽hSPAR通过其C末端（hSPAR-C）抑制E3连接酶TRIM21介导的P27KIP1降解，导致P27KIP1在乳腺癌细胞中在细胞质中积累。此外，hSPAR/hSPAR-C还作为谷氨酰胺转运体SLC38A2表达的抑制剂，从而特异性降低癌细胞中的细胞谷氨酰胺水平。由此导致的谷氨酰胺剥夺依次触发细胞质中的P27KIP1向溶酶体的转位，在溶酶体中P27KIP1破坏Ragulator复合物并抑制mTORC1组装。在异种移植模型中，给予hSPAR或hSPAR-C可显著阻碍乳腺癌细胞增殖和肿瘤生长。这些发现将hSPAR定义为细胞谷氨酰胺水平的内在控制因子，以及一种抑制mTORC1组装的新型肿瘤抑制因子。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86da/11876615/9838e680e5a8/44318_2024_359_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86da/11876615/cf2513661080/44318_2024_359_Fig9_ESM.jpg
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3
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