PDF(Pubmed)
Abstract：
Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5\'-phosphate (PLP), is a crucial cofactor for DNA and amino acid metabolism. The inverse correlation between vitamin B6 and cancer risk has been observed in several studies, although dietary vitamin B6 intake sometimes failed to confirm this association. However, the molecular link between vitamin B6 and cancer remains elusive. Previous work has shown that vitamin B6 deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, suggesting that genome instability may correlate the lack of this vitamin to cancer. Here we provide evidence in support of this hypothesis. Firstly, we show that PLP deficiency, induced by the PLP antagonists 4-deoxypyridoxine (4DP) or ginkgotoxin (GT), promoted tumorigenesis in eye larval discs transforming benign RasV12 tumors into aggressive forms. In contrast, PLP supplementation reduced the development of tumors. We also show that low PLP levels, induced by 4DP or by silencing the sgllPNPO gene involved in PLP biosynthesis, worsened the tumor phenotype in another Drosophila cancer model generated by concomitantly activating RasV12 and downregulating Discs-large (Dlg) gene. Moreover, we found that RasV12 eye discs from larvae reared on 4DP displayed CABs, reactive oxygen species (ROS) and low catalytic activity of serine hydroxymethyltransferase (SHMT), a PLP-dependent enzyme involved in thymidylate (dTMP) biosynthesis, in turn required for DNA replication and repair. Feeding RasV12 4DP-fed larvae with PLP or ascorbic acid (AA) plus dTMP, rescued both CABs and tumors. The same effect was produced by overexpressing catalase in RasV12 DlgRNAi 4DP-fed larvae, thus allowing to establish a relationship between PLP deficiency, CABs, and cancer. Overall, our data provide the first in vivo demonstration that PLP deficiency can impact on cancer by increasing genome instability, which is in turn mediated by ROS and reduced dTMP levels.
摘要：
维生素B6是一种水溶性维生素，具有抗氧化特性。其催化活性形式，吡哆醛5'-磷酸（PLP），是DNA和氨基酸代谢的关键辅因子。在几项研究中已经观察到维生素B6与癌症风险之间的负相关，尽管膳食维生素B6的摄入有时未能证实这种关联。然而,维生素B6和癌症之间的分子联系仍然难以捉摸。先前的工作表明，维生素B6缺乏会导致果蝇和人类细胞的染色体畸变（CAB），这表明基因组不稳定可能将这种维生素的缺乏与癌症联系起来。在这里，我们提供了支持这一假设的证据。首先,我们表明PLP缺乏，由PLP拮抗剂4-脱氧吡哆醇（4DP）或银杏毒素（GT）诱导，促进眼部幼虫椎间盘的肿瘤发生，将良性RasV12肿瘤转化为侵袭性形式。相比之下,PLP补充减少了肿瘤的发展。我们还表明，低PLP水平，由4DP诱导或通过沉默参与PLP生物合成的sgllPNPO基因，在伴随激活RasV12和下调Discs-large（Dlg）基因而产生的另一种果蝇癌症模型中，肿瘤表型恶化。此外，我们发现在4DP上饲养的幼虫的RasV12眼盘显示CAB，活性氧（ROS）和丝氨酸羟甲基转移酶（SHMT）的低催化活性，一种参与胸苷酸（dTMP）生物合成的PLP依赖性酶，反过来又需要DNA复制和修复。用PLP或抗坏血酸（AA）加dTMP饲喂RasV124DP的幼虫，拯救了CAB和肿瘤。通过在RasV12DlgRNAi4DP喂养的幼虫中过表达过氧化氢酶产生相同的效果，从而允许建立PLP缺乏之间的关系，CAB,和癌症。总的来说,我们的数据提供了第一个体内证明PLP缺乏可以通过增加基因组不稳定性来影响癌症，其又由ROS和降低的dTMP水平介导。
