Fenton reactions drive nucleotide and ATP syntheses in cancer

Abstract

We present a computational study of tissue transcriptomic data of 14 cancer types to address: what may drive cancer cell division? Our analyses point to that persistent disruption of the intracellular pH by Fenton reactions may be at the root of cancer development. Specifically, we have statistically demonstrated that Fenton reactions take place in cancer cytosol and mitochondria across all the 14 cancer types, based on cancer tissue gene-expression data integrated via the Michaelis–Menten equation. In addition, we have shown that (i) Fenton reactions in cytosol of the disease cells will continuously increase their pH, to which the cells respond by generating net protons to keep the pH stable through a combination of synthesizing glycolytic ATPs and consuming them by nucleotide syntheses, which may drive cell division to rid of the continuously synthesized nucleotides; and (ii) Fenton reactions in mitochondria give rise to novel ways for ATP synthesis with electrons ultimately coming from H2O2, largely originated from immune cells. A model is developed to link these to cancer development, where some mutations may be selected to facilitate cell division at rates dictated by Fenton reactions.

Transcription regulation by DNA methylation under stressful conditions in human cancer

“…While these pathways can be activated by a wide range of conditions, one thing in common is: they can all be activated by intracellular stresses, particularly oxidative stress [20][21][22], and associated damages. Actually, all these pathways are strongly associated with responses to Fenton reactions as noted in our previous study [23]. Hence, we postulate that these pathways are transcriptionally regulated via DNA methylation in response to severe intracellular and micro-environmental oxidative stress.…”

“…The intracellular and micro-environments of cancer cells may have specific stresses of the following types: persistent hypoxia, severe oxidative stress and stresses induced by rising intracellular pH [23,[29][30][31]. We have previously demonstrated that persistent hypoxia will lead to a persistent gap in ATP demand and supply [32].…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…It is, therefore, not surprising that iron accumulation is often observed in tumor tissues. Recently, iron accumulation at sites of chronic inflammation was proposed as a root cause of malignancy (1). Excess Fe 2+ and H 2 O 2 participate in Fenton reactions, generating reactive oxygen species (ROS), •OH and OH-.…”

“…Excess Fe 2+ and H 2 O 2 participate in Fenton reactions, generating reactive oxygen species (ROS), •OH and OH-. Glycolytic ATP generation and nucleotide synthesis are increased to neutralize excess OH − , which drives DNA synthesis and cell division (1). Furthermore, hydroxyl radicals can cause changes that lead to persistent inflammation and cell survival/proliferation signals (1).…”

“…Glycolytic ATP generation and nucleotide synthesis are increased to neutralize excess OH − , which drives DNA synthesis and cell division (1). Furthermore, hydroxyl radicals can cause changes that lead to persistent inflammation and cell survival/proliferation signals (1). Yet, hydroxyl radicals can also damage lipids in the cell membrane triggering ferroptosis (2).…”