The sulfiredoxin-peroxiredoxin (Srx-Prx) axis in cell signal transduction and cancer development

Abstract

Redox signaling is a critical component of cell signaling pathways that are involved in the regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Peroxiredoxin (Prx) is a family of thiol-based peroxidase that acts as a regulator of redox signaling. Members of Prx family can act as antioxidants and chaperones. Sulfiredoxin (Srx) is an antioxidant protein that exclusively reduces over-oxidized typical 2-Cys Prx. Srx has different affinities for individual Prx and it also catalyzes the deglutathionylation of variety of substrates. Individual component of the Srx-Prx system plays critical role in carcinogenesis by modulating cell signaling pathways involved in cell proliferation, migration and metastasis. Expression levels of individual component of the Srx-Prx axis have been correlated with patient survival outcome in multiple cancer types. This review will summarize the molecular basis of differences in the affinity of Srx for individual Prx and the role of individual component of the Srx-Prx system in tumor progression and metastasis. This enhanced understanding of molecular aspects of Srx-Prx interaction and its role in cell signal transduction will help define the Srx-Prx system as a future therapeutic target in human cancer.

Keywords: Oncogene; Peroxiredoxin; Redox signaling; Sulfiredoxin; Tumorigenesis.

Figure 1

Sulfiredoxin specifically reduces hyperoxidized form of typical 2-Cys peroxiredoxins and acts as an on-off switch to keep the balance between antioxidant and chaperone function of Prxs.

Figure 2

Sulfiredoxin catalyzes deglutathionylation of a variety of substrates.

Figure 3

A model of Srx-Prx interaction showing how concave shaped active site of Srx interacts with Prx dimer.

Figure 4

Oxidative stress stimulates Sulfiredoxin expression by regulating AP-1 and Nrf2 activity.

Figure 5

Peroxiredoxin may act as tumor-suppressor or oncogene depending on the context of tumor type.