Physiological functions of GPx2 and its role in inflammation‐triggered carcinogenesis

Abstract

Mammalian glutathione peroxidases (GPxs) are reviewed with emphasis on the role of the gastrointestinal GPx2 in tumorigenesis. GPx2 ranks high in the hierarchy of selenoproteins, corroborating its importance. Colocalization of GPx2 with the Wnt pathway in crypt bases of the intestine and its induction by Wnt signals point to a role in mucosal homeostasis, but GPx2 might also support tumor growth when increased by a dysregulated Wnt pathway. In contrast, the induction of GPx2 by Nrf2 activators and the upregulation of COX2 in cells with a GPx2 knockdown reveal inhibition of inflammation and suggest prevention of inflammation‐mediated carcinogenesis. The Janus‐faced role of GPx2 has been confirmed in a mouse model of inflammation‐associated colon carcinogenesis (AOM/DSS), where GPx2 deletion increased inflammation and consequently tumor development, but decreased tumor size. The model further revealed a GPx2‐independent decrease in tumor development by selenium (Se) and detrimental effects of the Nrf2‐activator sulforaphane in moderate Se deficiency.

Distinct prognostic values of mRNA expression of glutathione peroxidases in non–small cell lung cancer

“…Overexpressed GPx1 reduced tumor growth, which indicates that it has a role in protecting against tumorigenesis 30. The dual role of GPx2 in tumorigenesis has been reviewed recently 9,31. Overexpression of GPx2 was observed in several tumors,32,33 including lung cancer,34 indicating that GPx2 may be an oncogene.…”

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

“…Gpx2 appears to play a complex role in colon carcinogenesis (114), where it inhibits inflammation-driven tumorigenesis (115), yet promotes growth of xenografted tumors (116). Loss of GPX2 leads to dedifferentiation of cells to a progenitorlike state (117).…”

Nutritional Countermeasures Targeting Reactive Oxygen Species in Cancer: From Mechanisms to Biomarkers and Clinical Evidence

“…The antitumorigenic effect of Se and selenoproteins for prostate cancer was then further supported in a mouse model (86) as well as in a study showing that the GPX1 polymorphism can play an important role in predisposition to prostate carcinogenesis (16). Similarly, GPX2 has been reported to inhibit carcinogenesis by exerting hydroperoxide removal and suppression of COX2 expression (26,44). In line, GPX1 knockout mice are highly sensitive to oxidative stress (78), and GPX2 knockout mice were found to be more susceptible to skin cancer upon c-irradiation (372).…”