Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis

Abstract

Alterations from the normal set of chromosomes are extremely common as cells progress toward tumourigenesis. Similarly, we expect to see disruption of normal cellular metabolism, particularly in the use of glucose. In this review, we discuss the connections between these two processes: how chromosomal aberrations lead to metabolic disruption, and vice versa. Both processes typically result in the production of elevated levels of reactive oxygen species, so we particularly focus on their role in mediating oncogenic changes.

Keywords: DNA damage; aneuploidy; glycolysis; metabolism; oxidative stress; reactive oxygen species.

Figure 1

A schematic depicting the Warburg effect in cancer cells. The diagram illustrates the distinct aspects of the Warburg effect in cancer cells, containing glycolysis, pentose pyruvate pathway, lactate fermentation, glutamine metabolism, reactive oxygen species (ROS) generation, Tri-Carboxylic Acid (TCA) cycle, intermediates from the TCA cycle to synthesize lipids, and use of mutations in the TCA cycle (highlighted red) to synthesize oncometabolites. Important metabolic pathways are highlighted in yellow and important enzyme-regulating steps in glycolysis are highlighted in purple. Red lines with blunt ends indicate an inhibitory mode of action.

Figure 2

Overview of chromosomal instability (CIN) effects on metabolism. (1) The onset of aneuploidy brings about several cellular consequences including (2) proteomic imbalances [50], which can lead to (3) endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) mechanisms [89]. This leads to (4) increased mitochondrial activity due to increased energy demands and ROS production, which brings about (5) more DNA damage and protein oxidation. These lead to stress and damage to mitochondria, the ER and DNA. (6) DNA damage is repaired by poly (ADP-ribose) polymerase (PARP) activity, which uses NAD+, putting more stress on mitochondria, which results in more ROS [81]. (7) More DNA damage results in more mitotic errors, which increases cellular diversity.

Figure 3

Metabolic disruption can cause aneuploidy. Disturbances in energy metabolism lead to a buildup of pathological ROS. This can play a part in aberrant mitosis via several ways, such as disruptions to spindle checkpoint proteins [101,102], centrosome amplification [104,105], DNA breaks [101], and disturbances to telomeres [108].