Tumor cells fuel their metabolism with
glucose and
glutamine to meet the bioenergetic and biosynthetic demands of proliferation.
Hypoxia and oncogenic mutations drive glycolysis, with the
pyruvate to
lactate conversion being promoted by increased expression of
lactate dehydrogenase A and inactivation of
pyruvate dehydrogenase. The NAD+ pool is consecutively regenerated and supports the high glycolytic flux required to produce anabolic intermediates. Glutaminolysis provides metabolic intermediates such as
alpha-ketoglutarate to feed and thereby maintain the tricarboxylic acid cycle as a biosynthetic hub. Glycolysis and glutaminolysis share the capacity to generate
NADPH, from the pentose phosphate pathway and through the
malate conversion into
pyruvate, respectively. Both pathways ultimately lead to the secretion of
lactate. More than a
waste product,
lactate was recently identified as a major energy fuel in
tumors.
Lactate produced by hypoxic
tumor cells may indeed diffuse and be taken up by oxygenated
tumor cells. Preferential utilization of
lactate for oxidative metabolism spares
glucose which may in turn reach hypoxic
tumor cells. Monocarboxylate transporter 1 regulates the entry of
lactate into oxidative
tumor cells. Its inhibition favors the switch from
lactate-fuelled respiration to glycolysis and consecutively kills hypoxic
tumor cells from
glucose starvation. Combination with
radiotherapy renders remaining cells more sensitive to irradiation, emphasizing how interference with
tumor cell metabolism may
complement current anticancer modalities.