Vitamin C deficiency, degenerative metabolism, and cancer

Vitamin C deficiency favors cancer in a lot of different ways, and excessive vitamin C is useful in fighting cancer.

One little recognized route by which a critical level of vitamin C deficiency may create an atmosphere that favors the creation and growth of cancer may be through under-hydroxylation of HIF-1alpha under conditions of sufficient oxygenation. First, iron is required for this reaction and it must be in the Fe2+ oxidation state. Low vitamin C contributes to higher ROS and possibly favors the Fe3+ state of this enzyme, inhibiting the hydroxylation. Low vitamin C may also reduce the conversion of Fe3+ to Fe2+ and thus the catalytic rate of the reaction.

Without prior hydroxylation, HIF1alpha cannot be targeted for ubiquitin-mediated destruction by the von Hippel Lindau adaptor protein. If enough HIF-1alpha survives, HIF targets are activated. This includes glucose transporters, key enzymes of glycolysis, lactic acid dehydrogenase, pyruvate dehydrogenase kinase, and a protein promoting selective mitophagy (BNIP3). The effect of these changes favors degenerative metabolism in which mitochondria are selectively degraded, glucose is fermented, with the production of lactic acid and harmful aldehydes, and simultaneously, the complete combustion of glucose is inhibited by the phosphorylation of pyruvate dehydrogenase in mitochondria that were not turned over.

When the tumor has reached a critical mass, HIF also promotes angiogenesis through VEGF. This favors the growth of tumors, and creates a “symbiotic” (cf. Semenza, J. Clin. Invest. 118:3835-3837) “organ” or “organism” with a gradient of specialized and interdependent functions, in which, for example, cells closer to the blood vessels are more “normal” and take up oxygen, fuels, and run oxidative phosphorylation, while cells further from blood vessels remain more hypoxic, express more HIF-1, produce and excrete copious lactic acid, some of which the oxygenated tumor cells take up, convert to pyruvate, and generate ATP through OXPHOS. This local recycling of lactate is reminiscent of fast twitch and slow twitch muscle fibers.

This idea depends on the in vivo Km of the enzyme for the proline hydroxylase that hydroxylates HIF-1alpha. The difficulty is always knowing the Km in vivo – in vitro Km’s are easy to measure, but the environment is foreign and so many cellular factors are missing, including of course possible substitutes for each of the key factors, including vitamin C.

Iron deficiency, oxo-glutarate deficiency, antioxidant network deficiencies, and an occasional single burst of free radicals could have much the same effect on HIF metabolism.

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