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ALKBH5-PYCR2正反馈回路通过脯氨酸合成促进胶质母细胞瘤中的神经前体细胞向间充质细胞转变。

ALKBH5-PYCR2 Positive Feedback Loop Promotes Proneural-Mesenchymal Transition Via Proline Synthesis In GBM.

作者信息

Li Li, Yang Mengting, Pu Xufeng, Tang Yu, Fei Fei, Li Zhangzuo, Hou Hanjin, Chen Qian, Wang Qiaowei, Wu Yuqing, Zhang Ying, Ren Caifang, Gong Aihua

机构信息

Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, Jiang Su Province, China.

Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiang Su Province, China.

出版信息

J Cancer. 2023 May 29;14(9):1579-1591. doi: 10.7150/jca.84213. eCollection 2023.

DOI:10.7150/jca.84213
PMID:37325047
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10266253/
Abstract

AlkB homolog 5, RNA demethylase (ALKBH5) is abnormally highly expressed in glioblastoma multiforme (GBM) and is negatively correlated with overall survival in GBM patients. In this study, we found a new mechanism that ALKBH5 and pyrroline-5-carboxylate reductase 2 (PYCR2) formed a positive feedback loop involved in proline synthesis in GBM. ALKBH5 promoted PYCR2 expression and PYCR2-mediated proline synthesis; while PYCR2 promoted ALKBH5 expression through the AMPK/mTOR pathway in GBM cells. In addition, ALKBH5 and PYCR2 promoted GBM cell proliferation, migration, and invasion, as well as proneural-mesenchymal transition (PMT). Furthermore, proline rescued AMPK/mTOR activation and PMT after silencing PYCR2 expression. Our findings reveal an ALKBH5-PYCR2 axis linked to proline metabolism, which plays an important role in promoting PMT in GBM cells and may be a promising therapeutic pathway for GBM.

摘要

AlkB同源物5，RNA去甲基化酶（ALKBH5）在多形性胶质母细胞瘤（GBM）中异常高表达，且与GBM患者的总生存期呈负相关。在本研究中，我们发现了一种新机制，即ALKBH5与吡咯啉-5-羧酸还原酶2（PYCR2）形成了一个参与GBM脯氨酸合成的正反馈环。ALKBH5促进PYCR2表达及PYCR2介导的脯氨酸合成；而PYCR2通过GBM细胞中的AMPK/mTOR途径促进ALKBH5表达。此外，ALKBH5和PYCR2促进GBM细胞增殖、迁移和侵袭，以及促神经-间充质转化（PMT）。此外，在沉默PYCR2表达后，脯氨酸可挽救AMPK/mTOR激活和PMT。我们的研究结果揭示了一个与脯氨酸代谢相关的ALKBH5-PYCR2轴，其在促进GBM细胞的PMT中起重要作用，可能是GBM一种有前景的治疗途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/935d9a731c6f/jcav14p1579g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/b7b51d324154/jcav14p1579g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/1584d6801666/jcav14p1579g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/78c564cd3921/jcav14p1579g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/a17ff9fa338c/jcav14p1579g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/669bd99f75e9/jcav14p1579g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/935d9a731c6f/jcav14p1579g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/b7b51d324154/jcav14p1579g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/1584d6801666/jcav14p1579g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/78c564cd3921/jcav14p1579g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/a17ff9fa338c/jcav14p1579g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/669bd99f75e9/jcav14p1579g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d27/10266253/935d9a731c6f/jcav14p1579g006.jpg

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[1]
ALKBH5-PYCR2 Positive Feedback Loop Promotes Proneural-Mesenchymal Transition Via Proline Synthesis In GBM.

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[3]
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[4]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.

Nat Cell Biol. 2025-1

[2]
Emerging Roles and Mechanisms of RNA Modifications in Neurodegenerative Diseases and Glioma.

Cells. 2024-3-5

[3]
Subtype Transdifferentiation in Human Cancer: The Power of Tissue Plasticity in Tumor Progression.

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本文引用的文献

[1]
WZ35 inhibits gastric cancer cell metastasis by depleting glutathione to promote cellular metabolic remodeling.

Cancer Lett. 2023-2-28

[2]
Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models.

Front Oncol. 2022-11-2

[3]
Targeting PYCR2 inhibits intraperitoneal metastatic tumors of mouse colorectal cancer in a proline-independent approach.

Cancer Sci. 2023-3

[4]
The overexpression of GPX8 is correlated with poor prognosis in GBM patients.

Front Genet. 2022-8-17

[5]
Molecular mechanism by which CDCP1 promotes proneural-mesenchymal transformation in primary glioblastoma.

Cancer Cell Int. 2022-4-11

[6]
ALKBH5 promotes lung fibroblast activation and silica-induced pulmonary fibrosis through miR-320a-3p and FOXM1.

Cell Mol Biol Lett. 2022-3-12

[7]
Decreased RNA mA methylation enhances the process of the epithelial mesenchymal transition and vasculogenic mimicry in glioblastoma.

Am J Cancer Res. 2022-2-15

[8]
RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential.

J Hematol Oncol. 2022-1-21

[9]
MV1035 Overcomes Temozolomide Resistance in Patient-Derived Glioblastoma Stem Cell Lines.

Biology (Basel). 2022-1-4

[10]
ALKBH5 Facilitates Hypoxia-Induced Paraspeckle Assembly and IL8 Secretion to Generate an Immunosuppressive Tumor Microenvironment.

Cancer Res. 2021-12-1

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