Abstract
Mitochondria play multifaceted roles in malignant tumor progression. Beyond their bioenergetic role, mitochondria are essential for providing malignant cells a higher plasticity to face the harsh environmental conditions. Cell-autonomous metabolic deregulation of cancer cells, or metabolic adaptation to microenvironmental cues (lack of nutrients, stromal supply, hypoxia, etc.), represent the triggering event of mitochondria overexploitation to orchestrate nutrient sensing and upload, signaling, and redox circuits. As readout of their higher function, mitochondria produce high amounts of reactive oxygen species (ROS) that are functional for multiple signaling networks underlying tumor proliferation, survival, and metastatic process. To compensate for the higher rate of mitochondrial ROS production, cancer cells have evolved adaptive mechanisms to increase their antioxidant systems and to address ROS activating pathways useful for the tumor cell adaptation to environmental changes. As these properties are critical for cancer progression, mitochondrial ROS have recently become an attractive target for anti-cancer therapies. We discuss how understanding of mitochondrial function in the tumor-specific generation of ROS will impact on the development of novel redox-based targeted therapeutic strategies.
Highlights
Mitochondrial Reactive oxygen species (ROS): Source and Regulation in CancerTumor cells exhibit metabolic plasticity that provides them with a selective advantage to face harsh microenvironmental conditions
electron transport chain (ETC) complexes I and III by leaking free electrons lead to a mono-electronic O2 reduction to superoxide (O2-), which is readily reduced by superoxide dismutases (SODs) to hydrogen peroxide (H2O2)
The current idea is that cancer cells manifest a peculiar pattern of high ROS levels than non-transformed cells following the action of oncogenes, the loss-of-function of most tumor suppressor genes, the deregulation of metabolism, mitochondrial dysfunction, inflammatory burst, or genotoxic stress [1] and this is counteracted by a strong and highly regulated antioxidant machinery. mitochondrial ROS (mROS) are counteracted by a compartmentalized antioxidant apparatus not linked to the cytosolic one [2], with mitochondria using their own antioxidant enzymes, such as glutathione reductases, catalases, peroxidases, and other NADPH-generating sources
Summary
Mitochondrial ROS: Source and Regulation in CancerTumor cells exhibit metabolic plasticity that provides them with a selective advantage to face harsh microenvironmental conditions (e.g., hypoxia, acidosis, low nutrients availability). The current idea is that cancer cells manifest a peculiar pattern of high ROS levels than non-transformed cells following the action of oncogenes, the loss-of-function of most tumor suppressor genes, the deregulation of metabolism, mitochondrial dysfunction, inflammatory burst, or genotoxic stress [1] and this is counteracted by a strong and highly regulated antioxidant machinery.
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