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.
Highlights
Glioblastoma is a highly aggressive primary brain tumor with less than 15 months of median patient survival[1]
PERK-mediated secretion of proteins under hypoxia In order to determine which unfolded protein response (UPR) branch is active in glioblastoma under hypoxic conditions, LN308 and LN229 glioblastoma cells were treated with 1% O2 and the UPR pathway was analyzed
By investigating the secretome of glioblastoma, we have identified a new function of the UPR sensor PERK in the mediation of the expression and cleavage of peptidylglycine α-amidating monooxygenase (PAM)
Summary
Glioblastoma is a highly aggressive primary brain tumor with less than 15 months of median patient survival[1]. Reasons behind this poor prognosis include a high rate of angiogenesis, diffuse growth and modulation of the tumor microenvironment. PERK is one of the three unfolded protein response (UPR) sensors that become activated under endoplasmic reticulum stress conditions and functions to reduce the accumulation of misfolded proteins within the ER. It oligomerizes upon detection of misfolded proteins and is activated by auto-phosphorylation at threonine 980 on its cytosolic domain. PERK has been found to be involved in the secretion of collagen, insulin and generation of damage-associated molecular patterns (DAMPs)[6,7]
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