Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.
Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.
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DOI：
10.1002/cam4.349
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发表时间：
2015-02
期刊：
影响因子：
4
通讯作者：
Dachs, Gabi U.
中科院分区：
文献类型：
--
作者：
Campbell, Elizabeth J.;Vissers, Margreet C. M.;Bozonet, Stephanie;Dyer, Arron;Robinson, Bridget A.;Dachs, Gabi U.
缺氧诱导因子-1（HIF-1）控制细胞对缺氧微环境的适应，并与增殖性、转移性和治疗抗性肿瘤表型相关。HIF-1水平和转录活性受脯氨酸和天冬酰胺羟化酶调节，这需要抗坏血酸作为辅因子。补充抗坏血酸在体外降低了HIF-1的激活，但在相关动物模型中只有有限的数据。没有关于抗坏血酸生理水平对HIF活性和肿瘤生长的影响的信息，这在本研究中进行了测量。在B16-F10黑色素瘤或刘易斯肺癌（LL/2）皮下肿瘤生长之前和期间，在C57 BL/6 Gulo−/−小鼠（人类抗坏血酸盐依赖性病症的模型）的饮用水中补充3300 mg/L、330 mg/L或33 mg/L的抗坏血酸盐。随着抗坏血酸摄入量的增加，肿瘤中的抗坏血酸水平显著增加，野生型抗坏血酸水平的恢复导致B16-F10（对数期P < 0.001）和LL/2肿瘤（滞后生长P <0.001，对数期P < 0.05）的生长减少。在两种肿瘤模型中，随着饮食中抗坏血酸补充量的增加，肿瘤中HIF-1α蛋白水平降低（P < 0.001）。类似地，在B16-F10和LL/2肿瘤中，肿瘤抗坏血酸与HIF-1靶蛋白CA-IX、GLUT-1和VEGF的水平呈负相关（P < 0.05）。抗坏血酸组之间的坏死程度相似，但在模型之间不同（B16-F10为30%，LL/2为21%），表明抗坏血酸不影响肿瘤缺氧。我们的数据支持这一假设，即最佳细胞内抗坏血酸水平的恢复通过调节HIF-1通路活性来降低肿瘤生长。
Hypoxia-inducible factor-1 (HIF-1) governs cellular adaption to the hypoxic microenvironment and is associated with a proliferative, metastatic, and treatment-resistant tumor phenotype. HIF-1 levels and transcriptional activity are regulated by proline and asparagine hydroxylases, which require ascorbate as cofactor. Ascorbate supplementation reduced HIF-1 activation in vitro, but only limited data are available in relevant animal models. There is no information of the effect of physiological levels of ascorbate on HIF activity and tumor growth, which was measured in this study. C57BL/6 Gulo−/− mice (a model of the human ascorbate dependency condition) were supplemented with 3300 mg/L, 330 mg/L, or 33 mg/L of ascorbate in their drinking water before and during subcutaneous tumor growth of B16-F10 melanoma or Lewis lung carcinoma (LL/2). Ascorbate levels in tumors increased significantly with elevated ascorbate intake and restoration of wild-type ascorbate levels led to a reduction in growth of B16-F10 (log phase P < 0.001) and LL/2 tumors (lag growth P < 0.001, log phase P < 0.05). Levels of HIF-1α protein in tumors decreased as dietary ascorbate supplementation increased for both tumor models (P < 0.001). Similarly, tumor ascorbate was inversely correlated with levels of the HIF-1 target proteins CA-IX, GLUT-1, and VEGF in both B16-F10 and LL/2 tumors (P < 0.05). The extent of necrosis was similar between ascorbate groups but varied between models (30% for B16-F10 and 21% for LL/2), indicating that ascorbate did not affect tumor hypoxia. Our data support the hypothesis that restoration of optimal intracellular ascorbate levels reduces tumor growth via moderation of HIF-1 pathway activity.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
4.4
作者：
Mosdol, Annhild;Erens, Bob;Brunner, Eric J.
通讯作者：
Brunner, Eric J.
影响因子：
29.4
作者：
Berger, Mette M.
通讯作者：
Berger, Mette M.
影响因子：
11.2
作者：
Kuiper, Caroline;Molenaar, Ilona G. M.;Vissers, Margreet C. M.
通讯作者：
Vissers, Margreet C. M.
DOI：
10.1073/pnas.0804226105
发表时间：
2008-08-12
影响因子：
11.1
作者：
Chen, Qi;Espey, Michael Graham;Levine, Mark
通讯作者：
Levine, Mark