In the so-called canonical Wnt pathway, β-catenin is targeted for proteosomal degradation after phosphorylation by a complex that includes adenomatous polyposis coli (APC) and Axin. Wnt ligands bind to Frizzled receptors and abrogate β-catenin phosphorylation and degradation, leading to the initiation of gene transcription by stabilized β-catenin in the nucleus. Because hypoxia and activating mutations of the Wnt signaling pathway are common features of colorectal tumors, Verras et al. set out to determine whether lack of oxygen and other environmental stresses commonly observed in tumors, such as hypoglycemia and acidosis, affected the Wnt signaling pathway. In two different cancer cell lines containing intact Wnt regulatory pathways, they found that the amount of β-catenin protein was reduced by severe hypoxia or a combination of mild hypoxia and acidosis, and they showed that this reduction occurred through proteosomal degradation, although not through a pathway that involved APC or Axin. Intracellular and secreted amounts of Wnt3a (expressed and endogenous) were also lowered by severe hypoxia or mild hypoxia and acidosis, suggesting that, during hypoxia, decreases in Wnt led to decreases in β-catenin. Further investigation revealed that hypoxia inhibited Wnt3a interaction with the molecular chaperone glucose-regulated protein 78 (GRP78). Lack of GRP78 interaction impaired disulfide bond formation necessary for the proper processing of Wnt3a in the endoplasmic reticulum, and improperly folded Wnt3a was degraded in a proteosome-dependent manner. Finding that hypoxic regions in tumors were inversely correlated, although not perfectly, with Wnt3a staining, the authors speculated that stabilizing β-catenin mutations are prominent in colorectal tumors because they bypass the normal effects of hypoxia on Wnt regulation.
M. Verras, I. Papandreou, A. L. Lim, N. C. Denko, Tumor hypoxia blocks Wnt processing and secretion through the induction of endoplasmic reticulum stress. Mol. Cell. Biol. 28, 7212–7224 (2008). [Abstract] [Full Text]