Energy and Redox Homeostasis in Tumor Cells

Abstract

Cancer cells display abnormal morphology, chromosomes, and metabolism. This review will focus on the metabolism of tumor cells integrating the available data by way of a functional approach. The first part contains a comprehensive introduction to bioenergetics, mitochondria, and the mechanisms of production and degradation of reactive oxygen species. This will be followed by a discussion on the oxidative metabolism of tumor cells including the morphology, biogenesis, and networking of mitochondria. Tumor cells overexpress proteins that favor fission, such as GTPase dynamin-related protein 1 (Drp1). The interplay between proapoptotic members of the Bcl-2 family that promotes Drp 1-dependent mitochondrial fragmentation and fusogenic antiapoptotic proteins such as Opa-1 will be presented. It will be argued that contrary to the widespread belief that in cancer cells, aerobic glycolysis completely replaces oxidative metabolism, a misrepresentation of Warburg's original results, mitochondria of tumor cells are fully viable and functional. Cancer cells also carry out oxidative metabolism and generally conform to the orthodox model of ATP production maintaining as well an intact electron transport system. Finally, data will be presented indicating that the key to tumor cell survival in an ROS rich environment depends on the overexpression of antioxidant enzymes and high levels of the nonenzymatic antioxidant scavengers.

Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model

“…(12, 28, 29) Exposure of ATC cells to increasing doses of IR resulted in minimal perturbations in total cellular NADH levels (Supplemental Figure 2). In contrast, NAD+ levels increased within minutes of IR exposure and returned to baseline at 2hrs post irradiation (Supplemental Figure 2).…”

“…(6, 8) Although high levels of ROS are essential to achieving a therapeutic effect, basal ROS play an important role in tumorigenesis and metastasis. (11, 12) Because of this dual role, quantitative measurements of tumor cell and tumor ROS are important to maximize therapeutic efficacy and decrease normal tissue toxicity.…”

Expression of Inactive Glutathione Peroxidase 4 Leads to Embryonic Lethality, and Inactivation of theAlox15Gene Does Not Rescue Such Knock-In Mice

“…Dysregulation in the cellular redox homeostasis has been related to the pathogenesis of metabolic disorders (25), atherosclerosis (12), neurodegeneration (8) and cancer (13). The cellular redox state is determined by the counteracting activities of pro-and anti-oxidative enzymes and lipoxygenases (Alox) and glutathione peroxidases (Gpx) are key players in this network (7,20).…”

Redox homeostasis of breast cancer lineages contributes to differential cell death response to exogenous hydrogen peroxide

“…The greater amount of ROS is attributed to increased expression of enzymatic sources of ROS [3,4], increased production by non-enzymatic sources, e.g. abnormal mitochondrial respiration [5], impaired antioxidant activity or, more plausibly, a combination of these factors. In vivo studies have shown that mice lacking the intracellular antioxidant enzyme Cu-Zn Superoxide Dismutase (SOD1) develop hepatocarcinoma [6], while mice lacking Glutathione Peroxidase 1 (GPx1) and 2 (GPx2) develop intestine tumors [7], endorsing the concept of ROS as carcinogenic agents.…”