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蛋白激酶R样内质网激酶介导的肽基甘氨酸α-酰胺化单加氧酶表达促进胶质母细胞瘤血管生成。

PERK-mediated expression of peptidylglycine α-amidating monooxygenase supports angiogenesis in glioblastoma.

作者信息

Soni Himanshu, Bode Julia, Nguyen Chi D L, Puccio Laura, Neßling Michelle, Piro Rosario M, Bub Jonas, Phillips Emma, Ahrends Robert, Eipper Betty A, Tews Björn, Goidts Violaine

机构信息

Brain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Molecular Mechanisms of Tumor Invasion, Schaller Research Group, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

出版信息

Oncogenesis. 2020 Feb 13;9(2):18. doi: 10.1038/s41389-020-0201-8.

DOI:10.1038/s41389-020-0201-8
PMID:32054826
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7018722/
Abstract

PKR-like kinase (PERK) plays a significant role in inducing angiogenesis in various cancer types including glioblastoma. By proteomics analysis of the conditioned medium from a glioblastoma cell line treated with a PERK inhibitor, we showed that peptidylglycine α-amidating monooxygenase (PAM) expression is regulated by PERK under hypoxic conditions. Moreover, PERK activation via CCT020312 (a PERK selective activator) increased the cleavage and thus the generation of PAM cleaved cytosolic domain (PAM sfCD) that acts as a signaling molecule from the cytoplasm to the nuclei. PERK was also found to interact with PAM, suggesting a possible involvement in the generation of PAM sfCD. Knockdown of PERK or PAM reduced the formation of tubes by HUVECs in vitro. Furthermore, in vivo data highlighted the importance of PAM in the growth of glioblastoma with reduction of PAM expression in engrafted tumor significantly increasing the survival in mice. In summary, our data revealed PAM as a potential target for antiangiogenic therapy in glioblastoma.

摘要

蛋白激酶R样内质网激酶（PERK）在包括胶质母细胞瘤在内的多种癌症类型的血管生成诱导中发挥着重要作用。通过对用PERK抑制剂处理的胶质母细胞瘤细胞系的条件培养基进行蛋白质组学分析，我们发现肽基甘氨酸α-酰胺化单加氧酶（PAM）的表达在缺氧条件下受PERK调节。此外，通过CCT020312（一种PERK选择性激活剂）激活PERK增加了PAM的裂解，从而增加了作为从细胞质到细胞核的信号分子的PAM裂解胞质结构域（PAM sfCD）的产生。还发现PERK与PAM相互作用，提示其可能参与PAM sfCD的产生。敲低PERK或PAM可减少体外人脐静脉内皮细胞（HUVECs）形成管样结构。此外，体内数据突出了PAM在胶质母细胞瘤生长中的重要性，移植瘤中PAM表达的降低显著提高了小鼠的生存率。总之，我们的数据表明PAM是胶质母细胞瘤抗血管生成治疗的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/671a5a252d71/41389_2020_201_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/65dfce5c1db5/41389_2020_201_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/e84d8631060d/41389_2020_201_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/548a567b395b/41389_2020_201_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/c6c93b3aba7a/41389_2020_201_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/8603c66c7527/41389_2020_201_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/f6d896399a5b/41389_2020_201_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/d36101d532bb/41389_2020_201_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/671a5a252d71/41389_2020_201_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/65dfce5c1db5/41389_2020_201_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/e84d8631060d/41389_2020_201_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/548a567b395b/41389_2020_201_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/c6c93b3aba7a/41389_2020_201_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/8603c66c7527/41389_2020_201_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/f6d896399a5b/41389_2020_201_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/d36101d532bb/41389_2020_201_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ceb1/7018722/671a5a252d71/41389_2020_201_Fig8_HTML.jpg

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