Soluble Guanylate Cyclase β1 Subunit Represses Human Glioblastoma Growth

SIMPLE SUMMARY: A marked reduction in soluble guanylyl cyclase β1 (sGCβ1) transcript is characteristic for human glioma specimens. Restoring the expression of sGCβ1 inhibited the aggressive course of glioblastoma in an orthotopic xenograft mouse model. The present study is the first to reveal that sGCβ1 migrated into the nucleus and interacted with the promoter of the TP53 gene. sGCβ1 overexpression impacted signaling in glioblastoma multiforme, including the promotion of nuclear accumulation of p53, a marked reduction in cyclin-dependent kinase 6 (CDK6), and a significant decrease in integrin α6. Antitumor effect of sGCβ1 was not associated with enzymatic activity of sGC. ABSTRACT: Malignant glioma is the most common and deadly brain tumor. A marked reduction in the levels of sGC (soluble guanylyl cyclase) transcript in the human glioma specimens has been revealed in our previous studies. In the present study, restoring the expression of sGCβ1 alone repressed the aggressive course of glioma. The antitumor effect of sGCβ1 was not associated with enzymatic activity of sGC since overexpression of sGCβ1 alone did not influence the level of cyclic GMP. Additionally, sGCβ1-induced inhibition of the growth of glioma cells was not influenced by treatment with sGC stimulators or inhibitors. The present study is the first to reveal that sGCβ1 migrated into the nucleus and interacted with the promoter of the TP53 gene. Transcriptional responses induced by sGCβ1 caused the G0 cell cycle arrest of glioblastoma cells and inhibition of tumor aggressiveness. sGCβ1 overexpression impacted signaling in glioblastoma multiforme, including the promotion of nuclear accumulation of p53, a marked reduction in CDK6, and a significant decrease in integrin α6. These anticancer targets of sGCβ1 may represent clinically important regulatory pathways that contribute to the development of a therapeutic strategy for cancer treatment.