On why cancer cells require a great amount of glucose

The traditional thinking has been that cancer cells require a great amount of glucose to support their rapid growth, but the reality may be different. We have previously demonstrated that all cancer cells in The Cancer Genome Atlas harbor persistent Fenton reactions in their cytosol, which generate <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mrow> <mml:mrow><mml:msup><mml:mtext>OH</mml:mtext> <mml:mrow><mml:mo>-</mml:mo></mml:mrow> </mml:msup> </mml:mrow> </mml:mrow> </mml:mrow> </mml:math> and ultimately kill the cells by alkalosis if not neutralized timely. Here, we present data to show that (1) cancer cells uptake large amounts of glucose to produce sufficient levels of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mrow> <mml:mrow><mml:msup><mml:mi>H</mml:mi> <mml:mrow><mml:mo>+</mml:mo></mml:mrow> </mml:msup> </mml:mrow> </mml:mrow> </mml:mrow> </mml:math> ions to keep the cytosolic pH stable, hence keeping the cells viable; (2) <i>de novo</i> nucleotide biosynthesis represents the predominant acidifying pathway and gets on average the largest allocation of glucose metabolic flux among the 19 cancer types investigated; and (3) although the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mrow> <mml:mrow><mml:msup><mml:mi>H</mml:mi> <mml:mrow><mml:mo>+</mml:mo></mml:mrow> </mml:msup> </mml:mrow> </mml:mrow> </mml:mrow> </mml:math> ions produced by nucleotide biosynthesis and other acidifiers keep the cells alive, the synthesized nucleotides drive cancerous cell proliferation. Taken together, it is not that cancerous cell division requires high levels of glucose imports, instead it is the life-saving nucleotide syntheses that drive cell division. Understanding this causal relationship correctly is significant since it explains why cancers depend so heavily on glucose but not on other nutrients. More importantly, this realization may lead to fundamentally novel and more effective ways to treat cancer.