The Collagen-Prolyl Hydroxylases promote proliferation and invasion in GBM

Abstract

Abstract Glioblastoma Multiforme (GBM) is the most aggressive form of brain tumour, with a median survival time of just 14 months. Current standard therapy includes surgical excision, followed by chemotherapy and radiotherapy, however complete surgical excision is not usually possible due to the diffuse and infiltrative nature of the disease. To combat this, therapies inhibiting the invasion of leader migratory cells are an attractive area of research. The collagen prolyl-4 hydroxylases (C-P4Hs) are a family of proteins which catalyse the hydroxylation of proline residues on pre-pro-collagen, leading to the formation of the stable triple-helical structure of functional collagen. Collagen is a highly abundant protein, and important in several oncogenic cellular processes including proliferation, invasion and migration. We hypothesis that by inhibiting the C-P4Hs, the pro-tumorigenic effect of collagen will be inhibited in GBM. To explore this, we treated cells with ethyl 3,4-dihydroxybenzoate (EDHB) (a C-P4H inhibitor) and observed the resultant effect in GBM cells lines and primary cells through proliferation assays and 3D tumour spheroid invasion assays. Our results indicate that the addition of EDHB significantly reduces proliferation and invasion in both cell lines and primary GBM samples. Furthermore, we show that the C-P4Hs are upregulated in hypoxic conditions, which are commonly found in the clinical tumour microenvironment. Our study reveals that the C-P4H proteins may be an attractive therapeutic target to reduce invasion and proliferation and may be especially attractive as adjuvants with a cytotoxic agent such as temozolomide.