The Redox Regulation of Thiol Dependent Signaling Pathways in Cancer

Abstract

Reactive oxygen species (ROS) play a central role as second messengers in many signal transduction pathways, where they can post-translationally modify proteins via the oxidation of redox sensitive cysteine residues. The range of cellular processes under redox regulation is extensive and includes both the proliferative and apoptotic pathways. Control of the cellular redox environment is therefore essential for normal physiological function and perturbations to this redox balance are characteristic of many pathological states. Oxidative stress is particularly prevalent in cancer, where many malignant cell types possess an abnormal redox metabolism involving down-regulation of antioxidant enzymes and impaired mitochondrial function. This provides a major opportunity to design therapeutic strategies to selectively target cancer cells based on their redox profile. This review will provide a background to this emerging field by summarizing the known redox biochemistry of ROS signaling. The mechanisms of ROS generation by the action of oxidoreductases and nitric oxide synthases will be discussed in conjunction with the cell's major antioxidant defenses, with special emphasis placed on the subcellular location of these redox reactions. The effect of ROS on proliferation and apoptosis will be examined by looking at interactions with transcription factors and the Akt, TNF and MAPK signaling pathways. The review will also outline the major differences in redox metabolism between cancer cells and their non-malignant counterparts. Although the full extent of the ROS regulation of signaling pathways is only beginning to be mapped, early indications are that this paradigm will provide new therapeutic targets for cancer therapy.

Identification of a Dithiol-disulfide Switch in Collapsin Response Mediator Protein 2 (CRMP2) That Is Toggled in a Model of Neuronal Differentiation

“…Refs. [43][44][45]. For instance, a transcript variant (TXNRD1_v3) of the selenoprotein thioredoxin reductase 1 encodes an atypical N-terminal Grx domain.…”

Many forks in the path: cycling with FoxO

“…Indeed, most chemotherapeutic drugs are reported to arrest or delay cell cycle progression, and if the DNA damage or other cellular defects are extensive, the cell will undergo either apoptosis or cellular senescence (Lukas et al, 2004;Bartkova et al, 2005). Moreover, cancer cells may be considered to display an enhanced or higher level of basal stress, such as increased levels of reactive oxygen species or stress kinase activity, and it is precisely the deregulation of cell cycle checkpoints that allow cancer cells to tolerate such cellular conditions, while simultaneously promoting genomic instability and tumour progression (Giles, 2006;Wu, 2006;Fruehauf and Meyskens, 2007). One such mechanism by which cancer cells can tolerate cellular stress is the deactivation of FoxO3a, which would be anticipated to be activated by oxidative stress and stress kinases, both of which may converge through c-Jun N-terminal kinase-mediated phosphorylation of FoxO3a (Essers et al, 2004(Essers et al, , 2005Vogt et al, 2005;Huang and Tindall, 2007).…”

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

“…ROS-induced mutagenesis is an early causative factor in carcinogenesis, and ROS-mediated mitogenic signaling and redox modulation of apoptotic and survival pathways contribute to malignant transformation and progression [1][2][3][4]. ROS production from mitochondrial and other sources is increased in cancer cells leading to alterations of *Address correspondence to: Georg T. Wondrak, Ph.D., University of Arizona, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724 USA, E-mail: E-mail: wondrak@pharmacy.arizona.edu, Telephone: 520-6269017, FAX: 520-6268567.…”

“…For example, constitutive activation of nuclear factor κB signaling in human melanoma cells occurs as a result of autocrine generation of ROS contributing to proliferative signaling and the notorious resistance of melanoma cells to induction of apoptosis by chemotherapeutic agents [8,9]. In addition to substantiating the emerging role of the cellular redox environment in the general regulation of proliferation, differentiation, and survival [10], recent research has revealed the differential redox control of proliferation and viability in nontransformed versus malignant cells [1,2,6,11]. For example, in nontransformed NIH 3T3 cells, constitutive ROS production occurs at low levels, whereas in CT26 colon and Hepa 1-6 liver tumor cells, high concentrations of ROS, close to the threshold of cytotoxicity, are produced by mitochondria.…”