The Tumorigenic Roles of the Cellular REDOX Regulatory Systems

Abstract

The cellular REDOX regulatory systems play a central role in maintaining REDOX homeostasis that is crucial for cell integrity, survival, and proliferation. To date, a substantial amount of data has demonstrated that cancer cells typically undergo increasing oxidative stress as the tumor develops, upregulating these important antioxidant systems in order to survive, proliferate, and metastasize under these extreme oxidative stress conditions. Since a large number of chemotherapeutic agents currently used in the clinic rely on the induction of ROS overload or change of ROS quality to kill the tumor, the cancer cell REDOX adaptation represents a significant obstacle to conventional chemotherapy. In this review we will first examine the different factors that contribute to the enhanced oxidative stress generally observed within the tumor microenvironment. We will then make a comprehensive assessment of the current literature regarding the main antioxidant proteins and systems that have been shown to be positively associated with tumor progression and chemoresistance. Finally we will make an analysis of commonly used chemotherapeutic drugs that induce ROS. The current knowledge of cancer cell REDOX adaptation raises the issue of developing novel and more effective therapies for these tumors that are usually resistant to conventional ROS inducing chemotherapy.

Figure 1

The cellular antioxidant systems. Tumor progression induces increasing oxidative stress. Cells have several antioxidant systems to directly inactivate ROS (e.g., Trx peroxidases, GSH peroxidases, catalase, and SOD) as well as REDOX regulatory systems that recycle/reactivate the ROS scavenging proteins and other REDOX sensitive proteins (e.g., PTPs, PTEN, and transcription factors).

Figure 2

Sources of ROS in cancer. A number of intrinsic and extrinsic factors contribute to oxidative stress within the tumor as illustrated in the figure.

Figure 3

Antioxidant systems in cancer. Cancer cells undergo REDOX adaptation to survive and proliferate in an environment with increasing oxidative stress. Regulation of ROS levels by the cellular antioxidant systems is crucial to maintain a proliferative and mutagenic phenotype (associated with low/moderate levels of ROS) and avoid apoptosis or senescence (associated with high levels of ROS).