Pyridoxal phosphate (PLP) or vitamin B6 is produced by Pyridoxal kinase (PDXK) enzyme. We recently demonstrated in Drosophila that PLP deficiency caused by dPdxk1 mutation or PLP inhibitors results in chromosome aberrations (CABs), a well-known tumorigenic factor, and hyperglycemia. Interestingly, we demonstrated that this two phenotypes are correlated as high glucose causes CABs in dPdxk1 mutants. Also in human cells PDXK depletion causes CABs that are increased by glucose treatment, suggesting that the clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. Starting from these findings and based on many studies showing that diabetic individuals have an increased cancer risk we wondered whether PLP deficiency can be considered one of the factors that lead from diabetes to cancer. Thus, this proposal is aimed at verifying if low PLP levels are genotoxic in diabetic cells and to investigating the mechanisms though which PLP prevents CAB formation in diabetic cells. Thus, we will first evaluate chromosome damage in PLP depleted cells from two different Drosophila models of type 2 diabetes. Then, we will test whether Advanced Glycation end products (AGEs), that are genotoxic compounds whose formation is increased by high glucose levels and decreased by PLP, are responsible for DNA damage in PLP depleted diabetic cells.
To establish whether PLP can protect from chromosome damage in diabetic cells may impact on several lines of research: from studies on the role of PLP in the diet and cancer in general and in diabetes in particular, to the deeper investigation of which -among the numerous reactions where PLP serves as co-enzyme- may be more relevant in the mechanism(s) of CABs formation. In addition, the rationale to study the effect of PLP supplementation and cancer incidence in diabetic patients will be also set if the role of PLP in preventing/protecting chromosome damage in the presence of high
glucose concentrations will be firmly established (see https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/). Consequently,
these studies can be the starting point for setting therapies that limit the risk of cancer caused by CABs in patients with diabetes.
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