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

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PERK-mediated expression of peptidylglycine α-amidating monooxygenase supports angiogenesis in glioblastoma.
Oncogenesis ( IF 5.9 ) Pub Date : 2020-02-13 , DOI: 10.1038/s41389-020-0201-8
Himanshu Soni _{1,

2} , Julia Bode ₂ , Chi D L Nguyen ₃ , Laura Puccio ₁ , Michelle Neßling ₄ , Rosario M Piro _{5,

6,

7} , Jonas Bub ₁ , Emma Phillips ₁ , Robert Ahrends _{3,

8} , Betty A Eipper ₉ , Björn Tews ₂ , Violaine Goidts ₁

Affiliation

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.

中文翻译：

PERK介导的肽基甘氨酸α酰胺化单加氧酶的表达支持胶质母细胞瘤中的血管生成。

PKR样激酶（PERK）在各种类型的癌症（包括成胶质细胞瘤）的诱导血管生成中起重要作用。通过对用PERK抑制剂处理的胶质母细胞瘤细胞系中条件培养基的蛋白质组学分析，我们发现在低氧条件下，肽基甘氨酸α-酰胺化单加氧酶（PAM）的表达受PERK调节。此外，经由CCT020312（PERK选择性激活剂）的PERK激活增加了裂解作用，因此产生了PAM裂解的胞质结构域（PAM sfCD），该结构起从细胞质到细胞核的信号分子的作用。还发现PERK与PAM相互作用，表明可能参与了PAM sfCD的产生。敲除PERK或PAM可减少HUVEC在体外形成管子的过程。此外，体内数据强调了PAM在胶质母细胞瘤生长中的重要性，同时降低了移植瘤中PAM的表达，从而显着提高了小鼠的存活率。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标。

更新日期：2020-02-13

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