UBIAD1 redox enzyme inactivation as a new strategy to inhibit tumor angiogenesis

Angiogenesis, which consists in the growth of new blood vessels from pre-existing ones, is a hallmark of cancer. In contrast with the expectations, anti-angiogenic drugs suffer from scarce efficacy demanding for alternative anti-angiogenic approaches. Redox signalling is emerging as a major determinant of cancer growth and endothelial cell homeostasis. Nevertheless its role in tumor angiogenesis remains unexplored. Previous studies from the host lab showed that UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is one of the few antioxidant enzymes that regulate redox state in endothelial cells and play a critical role during developmental angiogenesis. We hypothesize that the impairment of UBIAD1-mediated antioxidant response in tumor vessels represents an innovative approach to treat tumor angiogenesis. Aim of the proposal is to demonstrate that UBIAD1 loss in tumor ECs leads to oxidative stress and then cell death, thus blocking tumor angiogenesis and, eventually, tumor growth and metastasis in vivo. Here we will evaluate the impact of UBIAD1 inactivation on the angiogenic capacity of tumor ECs in vitro and on tumor angiogenesis in vivo. We believe the accomplishment of this proposal will set the basis for the development of pharmacological inhibitors of UBIAD1 to be used in combination with current anti-angiogenic drugs to achieve a more effective inhibition of tumor angiogenesis and eventually tumor growth and metastasis.