SOD2 and Cancer: The Enzyme’s Role in Tumor Metabolism

Superoxide dismutase 2 (SOD2) is a mitochondrial enzyme that manages oxidative stress and influences tumor metabolism. Changes in its expression affect cancer cell survival and proliferation, making it a potential target for therapy. Researchers are investigating how modulating SOD2 activity could impact tumor growth and treatment response.

Enzymatic Role in Oxidative Stress Control

SOD2 mitigates oxidative damage in mitochondria by converting superoxide radicals (O₂⁻) into hydrogen peroxide (H₂O₂) and oxygen (O₂). Mitochondria, as primary reactive oxygen species (ROS) producers, rely on this process to prevent oxidative stress that damages mitochondrial DNA, proteins, and lipids.

Beyond detoxification, hydrogen peroxide acts as a signaling molecule regulating proliferation, differentiation, and apoptosis. The balance between ROS generation and scavenging determines whether oxidative signals promote survival or cell death. In tumor biology, oxidative stress can drive oncogenesis or suppress tumor growth, depending on the context.

SOD2 also influences cancer metabolism. Altered expression affects the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, altering ATP production and biosynthetic precursor availability. Its role extends beyond ROS control, shaping cellular energy dynamics.

Changes in SOD2 Expression in Neoplastic Cells

Neoplastic cells frequently exhibit altered SOD2 expression, varying by tumor type, stage, and microenvironment. Many cancers, including breast, prostate, and lung, show reduced SOD2 levels, correlating with increased oxidative stress and genomic instability. This suppression is linked to SOD2 promoter hypermethylation, histone modifications, and oncogenic signaling. The resulting superoxide accumulation promotes DNA damage, mutations, and proliferation.

Conversely, aggressive tumors, particularly in advanced stages, sometimes upregulate SOD2 to adapt to oxidative stress. Increased hydrogen peroxide production activates redox-sensitive transcription factors like NF-κB and HIF-1α, driving angiogenesis, epithelial-to-mesenchymal transition (EMT), and apoptosis resistance. In glioblastomas and pancreatic cancer, higher SOD2 levels enhance mitochondrial resilience, aiding survival in hypoxic conditions.

The dual role of SOD2 suggests tumors regulate its expression based on metabolic and environmental demands. Some cancers adjust SOD2 levels dynamically, balancing oxidative stress mitigation with ROS-dependent proliferation. Experimental models show that forced SOD2 overexpression can either suppress or enhance tumor progression, highlighting its context-dependent effects.

Metabolic Consequences of Altered SOD2 Activity

Changes in SOD2 activity reshape cancer cell metabolism. Reduced SOD2 skews redox balance, leading to superoxide accumulation that disrupts the TCA cycle and oxidative phosphorylation. This shift forces cells toward glycolysis, even in oxygen-rich environments—a hallmark of the Warburg effect. Increased lactate production acidifies the tumor microenvironment, promoting invasion and immune evasion while fueling nearby fibroblasts. The metabolic shift away from mitochondrial respiration also reduces oxidative damage-induced apoptosis, enhancing tumor survival.

Elevated SOD2 expression increases hydrogen peroxide levels, influencing mitochondrial metabolism. Hydrogen peroxide modulates key metabolic enzymes like pyruvate dehydrogenase (PDH) and AMP-activated protein kinase (AMPK), shifting energy utilization toward oxidative metabolism. This can support tumor growth by maintaining ATP production and biosynthetic precursor availability. Some cancers exploit increased mitochondrial function to fuel anabolic pathways for sustained proliferation. Metastatic cells often rely on fatty acid oxidation, an adaptation that enhances survival in energy-limited environments like the bloodstream or distant metastatic sites.

Regulatory Factors Influencing SOD2

SOD2 expression and activity are shaped by genetic, epigenetic, and environmental factors. Transcription factors such as nuclear factor erythroid 2-related factor 2 (Nrf2) and forkhead box O3 (FOXO3) regulate SOD2 levels in response to oxidative stress. In cancer, disruptions in these pathways can suppress or overactivate SOD2 based on metabolic needs.

Epigenetic modifications, including DNA methylation and histone acetylation, further influence SOD2 expression. Hypermethylation of its promoter, observed in breast and colorectal cancers, leads to transcriptional silencing and increased oxidative stress. Conversely, histone acetylation can upregulate SOD2 in response to metabolic stress, allowing tumors to adjust redox balance. Post-translational modifications, such as lysine acetylation, also affect enzymatic activity, altering its role in mitochondrial oxidative stress management.