CB-01 * TARGETING COLLAGEN REGULATION IN GLIOBLASTOMA MULTIFORME

Abstract

Extracellular matrices (ECM) are quintessential complex structures that provide cells and tissues of functional support for cell adhesion and migration, cell-to-cell communication and differentiation. Collagens are fibrillar proteins that constitute the major component of ECM and have key structural roles. Intracellular maturation of collagen precursors, prior to secretion, is dependent on the hydroxylation of collagen proline residues. This reaction is mediated by collagen prolyl 4-hydroxylases (P3H and P4H families' enzymes) in the presence of α-ketoglutarate, oxygen, Fe2+ and ascorbate. It is already known that ECM and collagen prolyl-hydroxylases are important players in cancer migration and invasion, but little has been explored in brain tumours and hypoxia. We have focused our investigations on glioblastoma multiforme (GBM) using two independent and specific inhibitors of collagen prolyl-hydroxylases: Ethyl 3,4-dihydroxybenzoate (EDHB), an α-ketoglutarate competitor, and 3,4-Dehydro-DL-proline (L-Proline analogue). The presence of these inhibitors showed a dramatic reduction in cell proliferation in a panel of established GBM cell lines. Similar results were obtained in primary cell lines from GBM tumours and melanoma brain metastasis. The mechanisms behind these effects are independent of apoptosis and we are currently exploring the role of autophagy and cell cycle arrest as possible other mechanisms. Surprisingly, even in low oxygen concentration (1%) there was a significant reduction in proliferation. Collagen regulation and its role in cell proliferation in both normoxic and hypoxic conditions will be discussed as a potential new therapeutic strategy for GBMs.