Aaron K. Holley

Manganese Superoxide Dismutase: Guardian of the Powerhouse

The mitochondrion is vital for many metabolic pathways in the cell, contributing all or important constituent enzymes for diverse functions such as β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis. The mitochondrion is also a major site of reactive oxygen species (ROS) production in the cell. Aberrant production of mitochondrial ROS can have dramatic effects on cellular function, in part, due to oxidative modification of key metabolic proteins localized in the mitochondrion. The cell is equipped with myriad antioxidant enzyme systems to combat deleterious ROS production in mitochondria, with the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) acting as the chief ROS scavenging enzyme in the cell. Factors that affect the expression and/or the activity of MnSOD, resulting in diminished antioxidant capacity of the cell, can have extraordinary consequences on the overall health of the cell by altering mitochondrial metabolic function, leading to the development and progression of numerous diseases. A better understanding of the mechanisms by which MnSOD protects cells from the harmful effects of overproduction of ROS, in particular, the effects of ROS on mitochondrial metabolic enzymes, may contribute to the development of novel treatments for various diseases in which ROS are an important component.

Manganese superoxide dismutase: beyond life and death

Manganese superoxide dismutase (MnSOD) is a nuclear-encoded antioxidant enzyme that localizes to the mitochondria. Expression of MnSOD is essential for the survival of aerobic life. Transgenic mice expressing a luciferase reporter gene under the control of the human MnSOD promoter demonstrate that the level of MnSOD is reduced prior to the formation of cancer. Overexpression of MnSOD in transgenic mice reduces the incidences and multiplicity of papillomas in a DMBA/TPA skin carcinogenesis model. However, MnSOD deficiency does not lead to enhanced tumorigenicity of skin tissue similarly treated because MnSOD can modulate both the p53-mediated apoptosis and AP-1-mediated cell proliferation pathways. Apoptosis is associated with an increase in mitochondrial levels of p53 suggesting a link between MnSOD deficiency and mitochondrial-mediated apoptosis. Activation of p53 is preventable by application of a SOD mimetic (MnTE-2-PyP5+). Thus, p53 translocation to mitochondria and subsequent inactivation of MnSOD explain the observed mitochondrial dysfunction that leads to transcription-dependent mechanisms of p53-induced apoptosis. Administration of MnTE-2-PyP5+ following apoptosis but prior to proliferation leads to suppression of protein carbonyls and reduces the activity of AP-1 and the level of the proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Remarkably, the incidence and multiplicity of skin tumors are drastically reduced in mice that receive MnTE-2-PyP5+ prior to cell proliferation. The results demonstrate the role of MnSOD beyond its essential role for survival and suggest a novel strategy for an antioxidant approach to cancer intervention.

MANGANESE SUPEROXIDE DISMUTASE VS. P53: REGULATION OF MITOCHONDRIAL ROS

Coordination of mitochondrial and nuclear activities is vital for cellular homeostasis, and many signaling molecules and transcription factors are regulated by mitochondria-derived reactive oxygen species (ROS) to carry out this interorganellar communication. The tumor suppressor p53 regulates myriad cellular functions through transcription-dependent and -independent mechanisms at both the nucleus and mitochondria. p53 affect mitochondrial ROS production, in part, by regulating the expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD). Recent evidence suggests mitochondrial regulation of p53 activity through mechanisms that affect ROS production, and a breakdown of communication amongst mitochondria, p53, and the nucleus can have broad implications in disease development.

Manganese superoxide dismutase versus p53: the mitochondrial center

Mitochondria are important sites of myriad metabolic activities. The actions of mitochondria must be carefully synchronized with other processes in the cell to maintain cellular homeostasis. Interorganellar communication between mitochondria and the nucleus is key for coordination of these cellular functions. Numerous signaling proteins and transcription factors are affected by reactive oxygen species and aid interorganellar communication. p53 is an important tumor suppressing protein that regulates many cellular activities, such as cell cycle regulation, DNA repair, and programmed cell death. p53 carries out these functions through both transcription‐dependent and transcription‐independent routes at mitochondria and the nucleus. Manganese superoxide dismutase (MnSOD), a p53‐regulated gene that is a vital antioxidant enzyme localized in the matrix of mitochondria, scavenges reactive oxygen species. Recent studies suggest that mitochondria can regulate p53 activity and that assaults on the cell that affect mitochondrial ROS production and mitochondrial function can influence p53 activity. Cross‐talk between mitochondria and p53 is important in normal cellular functions, and a breakdown in communication among mitochondria, p53, and the nucleus may have serious consequences in disease development.

RelB regulates manganese superoxide dismutase gene and resistance to ionizing radiation of prostate cancer cells

Radiation therapy is in the front line for treatment of localized prostate cancer. However, a significant percentage of patients have radiation‐resistant disease. The NF‐κB pathway is an important factor for radiation resistance, and the classical (canonical) pathway is thought to confer protection of prostate cancer cells from ionizing radiation. Recently, the alternative (non‐canonical) pathway, which is involved in prostate cancer aggressiveness, has also been shown to be important for radiation resistance in prostate cancer. The alternative NF‐κB pathway component RelB protects prostate cancer cells from the detrimental effects of ionizing radiation, in part, by stimulating expression of the mitochondria‐localized antioxidant enzyme manganese superoxide dismutase (MnSOD). Blocking RelB activation suppresses MnSOD expression and sensitizes prostate cancer cells to radiation. These results suggest that RelB‐mediated modulation of the antioxidant capacity of prostate cancer cells is an important mechanism of radiation resistance. Therefore, targeting RelB activation may prove to be a valuable weapon in the oncologists arsenal to defeat aggressive and radiation‐resistant prostate cancer.

KEAP1 Is a Redox Sensitive Target That Arbitrates the Opposing Radiosensitive Effects of Parthenolide in Normal and Cancer Cells

Elevated oxidative stress is observed more frequently in cancer cells than in normal cells. It is therefore expected that additional exposure to a low level of reactive oxygen species (ROS) will push cancer cells toward death, whereas normal cells might maintain redox homeostasis through adaptive antioxidant responses. We previously showed that parthenolide enhances ROS production in prostate cancer cells through activation of NADPH oxidase. The present study identifies KEAP1 as the downstream redox target that contributes to parthenolides radiosensitization effect in prostate cancer cells. In vivo, parthenolide increases radiosensitivity of mouse xenograft tumors but protects normal prostate and bladder tissues against radiation-induced injury. Mechanistically, parthenolide increases the level of cellular ROS and causes oxidation of thioredoxin (TrX) in prostate cancer cells, leading to a TrX-dependent increase in a reduced state of KEAP1, which in turn leads to KEAP1-mediated PGAM5 and Bcl-xL (BCL2L1) degradation. In contrast, parthenolide increases oxidation of KEAP1 in normal prostate epithelial cells, leading to increased Nrf2 (NFE2L2) levels and subsequent Nrf2-dependent expression of antioxidant enzymes. These results reveal a novel redox-mediated modification of KEAP1 in controlling the differential effect of parthenolide on tumor and normal cell radiosensitivity. Furthermore, they show it is possible to develop a tumor-specific radiosensitizing agent with radioprotective properties in normal cells.

Mitochondrial Superoxide Dismutase - Signals of Distinction

Mitochondrial superoxide dismutase (MnSOD) neutralizes the highly reactive superoxide radical (O(2)(˙-)), the first member in a plethora of mitochondrial reactive oxygen species (ROS). Over the past decades, research has extended the prevailing view of mitochondrion well beyond the generation of cellular energy to include its importance in cell survival and cell death. In the normal state of a cell, endogenous antioxidant enzyme systems maintain the level of reactive oxygen species generated by the mitochondrial respiratory chain. Mammalian mitochondria are important to the production of reactive oxygen species, which underlie oxidative damage in many pathological conditions and contribute to retrograde redox signaling from the organelle to the cytosol and nucleus. Mitochondria are further implicated in various metabolic and aging-related diseases that are now postulated to be caused by misregulation of physiological systems rather than pure accumulation of oxidative damage. Thus, the signaling mechanisms within mitochondria, and between the organelle and its environment, have gained interest as potential drug targets. Here, we discuss redox events in mitochondria that lead to retrograde signaling, the role of redox events in disease, and their potential to serve as therapeutic targets.

Curbing cancer's sweet tooth: Is there a role for MnSOD in regulation of the Warburg effect?

Reactive oxygen species (ROS), while vital for normal cellular function, can have harmful effects on cells, leading to the development of diseases such as cancer. The Warburg effect, the shift from oxidative phosphorylation to glycolysis, even in the presence of adequate oxygen, is an important metabolic change that confers many growth and survival advantages to cancer cells. Reactive oxygen species are important regulators of the Warburg effect. The mitochondria-localized antioxidant enzyme manganese superoxide dismutase (MnSOD) is vital to survival in our oxygen-rich atmosphere because it scavenges mitochondrial ROS. MnSOD is important in cancer development and progression. However, the significance of MnSOD in the regulation of the Warburg effect is just now being revealed, and it may significantly impact the treatment of cancer in the future.

Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

SIGNIFICANCE Radiation therapy is widely used for treatment of prostate cancer. Radiation can directly damage biologically important molecules; however, most effects of radiation-mediated cell killing are derived from the generated free radicals that alter cellular redox status. Multiple proinflammatory mediators can also influence redox status in irradiated cells and the surrounding microenvironment, thereby affecting prostate cancer progression and radiotherapy efficiency. RECENT ADVANCES Ionizing radiation (IR)-generated oxidative stress can regulate and be regulated by the production of proinflammatory mediators. Depending on the type and stage of the prostate cancer cells, these proinflammatory mediators may lead to different biological consequences ranging from cell death to development of radioresistance. CRITICAL ISSUES Tumors are heterogeneous and dynamic communication occurs between stromal and prostate cancer cells, and complicated redox-regulated mechanisms exist in the tumor microenvironment. Thus, antioxidant and anti-inflammatory strategies should be carefully evaluated for each patient at different stages of the disease to maximize therapeutic benefits while minimizing unintended side effects. FUTURE DIRECTIONS Compared with normal cells, tumor cells are usually under higher oxidative stress and secrete more proinflammatory mediators. Thus, redox status is often less adaptive in tumor cells than in their normal counterparts. This difference can be exploited in a search for new cancer therapeutics and treatment regimes that selectively activate cell death pathways in tumor cells with minimal unintended consequences in terms of chemo- and radio-resistance in tumor cells and toxicity in normal tissues.

p53 Regulation of Energy Metabolism and Mitochondria Regulation of p53 in Cancer Cells: An Insight into the Role of Manganese Superoxide Dismutase

Accumulated evidence suggests that p53 plays an important role in the regulation of metabolism and intracellular redox homeostasis through transcription-dependent and -independent mechanisms. Mitochondria, the power plant of cells, provide cells with ATP for their functions by regulating energy metabolism. In addition, as the byproducts of metabolism, reactive oxygen species (ROS) generated in the mitochondria can serve as signaling molecules to regulate p53 function. The regulation of p53 by mitochondria, especially redox-mediated regulation, may be involved in controlling the cellular switch between survival and death. The interplay between p53 and manganese superoxide dismutase (MnSOD), an important mitochondrial antioxidant enzyme, is an example of how nuclear and mitochondrial p53 coordinate their response to different levels of stress and contribute to the fate of cells.