Oxidative Stress in Cancer.

Area of Science:

• Biochemistry
• Oncology
• Cell Biology

Background:

• Reactive oxygen species (ROS) play a dual role in cancer evolution, capable of initiating tumorigenesis and promoting cell proliferation or inducing cell death.
• Tumor cells develop adaptive mechanisms to cope with high ROS levels, involving modifications in sulfur metabolism, NADPH production, and antioxidant transcription factor activity.

Purpose of the Study:

• To elucidate the complex roles of ROS in cancer initiation, progression, and metastasis.
• To investigate the metabolic and molecular adaptations employed by cancer cells to survive and thrive under oxidative stress.

Main Methods:

• Analysis of genetic alterations enabling cell survival under high ROS.
• Investigation of metabolic pathways, including the pentose phosphate pathway (PPP), for NADPH generation.
• Examination of antioxidant transcription factor activation and the role of AMP-activated protein kinase (AMPK).

Main Results:

• Genetic changes facilitate cancer cell survival by activating antioxidant transcription factors or increasing NADPH via the PPP during initiation.
• Tumor cells adapt to oxidative stress during progression and metastasis by upregulating NADPH production through various pathways.
• Key pathways for NADPH generation include the PPP, reductive glutamine metabolism, and folate metabolism, alongside AMPK activation.

Conclusions:

• ROS concentration dictates their effect on cancer, acting as both a driver and a cytotoxic agent.
• Metabolic reprogramming, particularly enhanced NADPH generation, is a critical adaptive strategy for cancer cells to manage oxidative stress throughout tumor evolution.
• Understanding these adaptive mechanisms offers potential therapeutic targets for cancer treatment.