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Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.

ABSTRACT: 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-1? 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.

SUBMITTER: Campbell EJ

PROVIDER: S-EPMC4329013 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.

Campbell Elizabeth J EJ Vissers Margreet C M MC Bozonet Stephanie S Dyer Arron A Robinson Bridget A BA Dachs Gabi U GU

Cancer medicine 20141030 2

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 le ...[more]

PMID: 25354695

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Project description:In solid tumors, HIF1 upregulates the expression of hundreds of genes involved in cell survival, tumor growth, and adaptation to the hypoxic microenvironment. HIF1 stabilization and activity are suppressed by prolyl and asparagine hydroxylases, which require oxygen as a substrate and ascorbate as a cofactor. This has led us to hypothesize that intracellular ascorbate availability could modify the hypoxic HIF1 response and influence tumor growth. In this study, we investigated the effect of variable intracellular ascorbate levels on HIF1 induction in cancer cells in vitro, and on tumor-take rate and growth in the Gulo-/- mouse. These mice depend on dietary ascorbate, and were supplemented with 3,300 mg/L, 330 mg/L, or 33 mg/L ascorbate in their drinking water, resulting in saturating, medium, or low plasma and tissue ascorbate levels, respectively. In Lewis lung carcinoma cells (LL/2) in culture, optimal ascorbate supplementation reduced HIF1 accumulation under physiological but not pathological hypoxia. LL/2, B16-F10 melanoma, or CMT-93 colorectal cancer cells were implanted subcutaneously into Gulo-/- mice at a range of cell inocula. Establishment of B16-F10 tumors in mice supplemented with 3,300 mg/L ascorbate required an increased number of cancer cells to initiate tumor growth compared with the number of cells required in mice on suboptimal ascorbate intake. Elevated ascorbate intake was also associated with decreased tumor ascorbate levels and a reduction in HIF1? expression and transcriptional activity. Following initial growth, all CMT-93 tumors regressed spontaneously, but mice supplemented with 33 mg/L ascorbate had lower plasma ascorbate levels and grew larger tumors than optimally supplemented mice. The data from this study indicate that improved ascorbate intake is consistent with increased intracellular ascorbate levels, reduced HIF1 activity and reduced tumor initiation and growth, and this may be advantageous in the management of cancer.

Project description:Parasites are fundamental components within all ecosystems, shaping interaction webs, host population dynamics and behaviour. Despite this, baseline data is lacking to understand the parasite ecology of many Arctic species, including the wolverine (Gulo gulo), a top Arctic predator and scavenger. Here, we combined traditional count methods (i.e. adult helminth recovery, where taxonomy was confirmed by molecular identification) with 18S rRNA high-throughput sequencing to document the wolverine parasite community. Further, we investigated whether the abundance of parasites detected using traditional methods were associated with host metadata, latitude, and longitude (ranging from the northern limit of the boreal forest to the low Arctic and Arctic tundra in Nunavut, Canada). Adult parasites in intestinal contents were identified as Baylisascaris devosi in 72% (n = 39) of wolverines and Taenia spp. in 22% (n = 12), of which specimens from 2 wolverines were identified as T. twitchelli based on COX1 sequence. 18S rRNA high-throughput sequencing on DNA extracted from faeces detected additional parasites, including a pseudophyllid cestode (Diplogonoporus spp. or Diphyllobothrium spp.), two metastrongyloid lungworms (Angiostrongylus spp. or Aelurostrongylus spp., and Crenosoma spp.), an ascarid nematode (Ascaris spp. or Toxocara spp.), a Trichinella spp. nematode, and the protozoan Sarcocystis spp., though each at a prevalence less than 13% (n = 7). The abundance of B. devosi significantly decreased with latitude (slope = -0.68; R2 = 0.17; P = 0.004), suggesting a northerly limit in distribution. We describe B. devosi and T. twitchelli in Canadian wolverines for the first time since 1978, and extend the recorded geographic distribution of these parasites ca 2000 km to the East and into the tundra ecosystem. Our findings illustrate the value of molecular methods in support of traditional methods, encouraging additional work to improve the advancement of molecular screening for parasites.

Dataset Information

Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.

Publications

Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.

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