GPx2 Suppression of H2O2 Stress Links the Formation of Differentiated Tumor Mass to Metastatic Capacity in Colorectal Cancer

Abstract

Colorectal tumorigenesis is accompanied by the generation of oxidative stress, but how this controls tumor development is poorly understood. Here, we studied how the H 2 O 2 -reducing enzyme glutathione peroxidase 2 (GPx2) regulates H 2 O 2 stress and differentiation in patient-derived "colonosphere" cultures. GPx2 silencing caused accumulation of radical oxygen species, sensitization to H 2 O 2 -induced apoptosis, and strongly reduced clone-and metastasis-forming capacity. Neutralization of radical oxygen species restored clonogenic capacity. Surprisingly, GPx2-suppressed cells also lacked differentiation potential and formed slow-growing undifferentiated tumors. GPx2 overexpression stimulated multilineage differentiation, proliferation, and tumor growth without reducing the tumor-initiating capacity. Finally, GPx2 expression was inversely correlated with H 2 O 2 -stress signatures in human colon tumor cohorts, but positively correlated with differentiation and proliferation. Moreover, high GPx2 expression was associated with early tumor recurrence, particularly in the recently identified aggressive subtype of human colon cancer. We conclude that H 2 O 2 neutralization by GPx2 is essential for maintaining clonogenic and metastatic capacity, but also for the generation of differentiated proliferating tumor mass. The results reveal an unexpected redox-controlled link between tumor mass formation and metastatic capacity. Cancer Res; 74(22); 6717-30. Ó2014 AACR.

CD95 ligand induces senescence in mismatch repair-deficient human colon cancer via chronic caspase-mediated induction of DNA damage

“…23 As ROS production can contribute to cellular senescence, we considered the possibility that CD95-induced senescence was due to ROS production. However, treatment with the ROS scavenger N -acetylcysteine increased the general clone-forming capacity (as we have shown before 24 ) but had no effect on CD95L-induced loss of clonogenic capacity (Supplementary Figure S4), indicating that ROS production is dispensable for CD95L-induced senescence.…”

“…Patient-derived colorectal cancer colonospheres; CR16, CRC26, CRC29, CRC47, L145, L146, L167, L169, and L193 24 were cultured in supplemented advanced DMEM/F12 (12634-010, ThermoFisher Scientific, Walthom, MA, USA) on low-adherent culture dishes. Basic-FGF (4 ng/ml) (100-18B, Peprotech, Rocky Hill, NJ, USA) was added freshly to the medium with every cell passaging.…”

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). Conversely, overexpression of GPX2 leads to cell differentiation, with increased proliferation and tumor-forming potential (117).…”

“…Loss of GPX2 leads to dedifferentiation of cells to a progenitorlike state (117). Conversely, overexpression of GPX2 leads to cell differentiation, with increased proliferation and tumor-forming potential (117). Selenium status has a complex role in mouse models of cancer, as demonstrated by studies showing that both selenium deficiency and selenium supplementation can reduce the tumor incidence in different mouse models (118,119).…”

Selenoproteins and Metastasis

“…Perhaps the best example is GPX2, which is highly expressed in gastrointestinal tissues and mostly examined in the context of colorectal cancer due to its upregulation in intestinal adenomas and in colon tumors (Florian et al, 2001). In a study using patient-derived colonosphere cultures, GPX2 silencing caused accumulation of reactive oxygen species, sensitization to H 2 O 2 -induced apoptosis, and strongly reduced metastases from primary tumors in the spleen to secondary tumors in the liver (Emmink et al, 2014). These cancer cells rely on GPX2 to keep ROS at optimal levels for metastatic capacity.…”