The biological active form of vitamin B6, pyridoxal 5-phosphate (PLP), is a coenzyme involved in more than 150 metabolic reactions; in addition, it works as antioxidant molecule by counteracting the formation of oxygen reactive species (ROS) and Advanced Glycation End products (AGEs). Reduced vitamin B6 availability modulates cancer risk, but underlying mechanisms are not completely elucidated. We previously demonstrated that low PLP levels induce chromosome aberrations (CABs) in Drosophila melanogaster and human cells. As CABs represent a well-known tumorigenic factor we hypothesized that DNA damage can be one of the mechanisms underlying the link between PLP availability and cancer. Taking advantage of the high conservation of main metabolic molecular pathways in flies, in this project we aim to verify this hypothesis, by investigating whether PLP depletion in Drosophila increases malignant behavior of Ras and Ras/Src cancers. To this purpose, we will generate these cancer models by employing the mosaic analysis with a repressible cell marker (MARCM) genetic strategy, and we will assess if the feeding of larvae with the PLP inhibitor 4-deoxypyrodoxine (4-DP) increases primary tumor growth and/or induces the formation of secondary tumors. Then, we will verify whether PLP depletion causes, at the same time, CABs in cancer tissues. Our second goal will be to elucidate the mechanisms through which DNA damage is generated. In particular, we will investigate whether PLP impacts on cancer as cofactor, antioxidant molecule or both. To this purpose, we will test in cancer tissues the activity of serine hydroxymethyltranferase (SHMT) a PLP-dependent enzyme involved in DNA metabolism, as well as the presence of AGEs. Based on preliminary data indicating a clear impact of PLP on the above-mentioned cancer models, we expect that this research will contribute to shed light on the mechanisms governing the relationship between vitamin B6, DNA damage and cancer.
We expect that the realization of this project will confirm our hypothesis according to which decreased levels of vitamin B6 can impact on cancer development/progression by inducing DNA damage (13). In addition, we expect to shed light on the mechanisms through which vitamin B6 protect from cancer. These results will add a piece of knowledge to the complex relationship between vitamin B6 and cancer. Although in developed countries PLP deficiency is a rare condition, as this vitamin is present in many different foods, low vitamin B6 levels are associated to certain human pathologies such as diabetes, celiac and renal diseases as well as to alcoholism and can represent the side effect of some drugs. Thus, knowing the cancer risks associated to PLP deficiency is crucial also in view of planning in the future personalized treatments.
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