Targeting Metabolism to Induce Cell Death in Cancer Cells and Cancer Stem Cells

Abnormal metabolism and the evasion of apoptosis are considered hallmarks of cancers. Accumulating evidence shows that cancer stem cells are key drivers of tumor formation, progression, and recurrence. A successful therapy must therefore eliminate these cells known to be highly resistant to apoptosis. In this paper, we describe the metabolic changes as well as the mechanisms of resistance to apoptosis occurring in cancer cells and cancer stem cells, underlying the connection between these two processes. 1. Introduction Cell proliferation involves the replication of all cellular contents with the required energy for this to happen. In normal cells, glucose participates in cellular energy production through glycolysis as well as through its complete catabolism via the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). In addition to glucose, glutamine is also required to feed the TCA cycle. Lipids, amino acids, and nucleotides necessary for the biosynthesis of the daughter cells are mostly provided by intermediate metabolites of these pathways. To prevent aberrant cell proliferation, these pathways are tightly regulated. However, cancer cells overcome these controls, in particular by acquiring genetic mutations leading to the activation of oncogenes (pten, myc) or loss of tumor suppressors (p53) [1]. For example, a major regulator of metabolism is phosphoinositol 3 kinase (PI3K). PI3K is activated by growth factors resulting in, among others, the activation of Akt and mTOR. This activation is necessary for both cell proliferation as well as glucose uptake and use. In addition to its role in glucose metabolism, this pathway also regulates the redirection of free amino acids to protein synthesis via the mTOR-signaling pathway. 2. Metabolic Modifications in Cancer Cells In contrast to normal cells, most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactate fermentation, even in the presence of oxygen, a less efficient metabolism compared to a low rate of glycolysis followed by mitochondrial oxidation of pyruvate [2]. Typically, rapidly proliferating tumor cells have glycolytic rates up to 200 times higher than those of their normal tissue of origin, even in the presence of oxygen [3]. This observation resulted in the development of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (PET) to detect glucose uptake and lactate production for tumor imaging. Pyruvate, which is at the crossroad between lactate production and OXPHOS, constitutes a key metabolic intermediate. In normal cells, the