PerspectiveCell Biology

Oxidative Stress and Cancer: A β-Catenin Convergence

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Science  20 May 2005:
Vol. 308, Issue 5725, pp. 1119-1120
DOI: 10.1126/science.1113356

The Wnt signaling pathway often seems indefatigable, acting at numerous times and places throughout both invertebrate and vertebrate development. Its influence is broad, directing processes as diverse as body axis formation, organogenesis, cell migration, and stem cell proliferation (1, 2). When Wnt ligands activate cell surface receptors, the proteolytic destruction of a remarkable cytoplasmic protein called β-catenin is halted. This key mediator of Wnt signaling is then free to move to the nucleus where it binds to and converts a family of transcriptional repressors called T cell factors (TCFs) into activators of gene expression (1, 2). Malfunction of this pathway can result in the abnormal stabilization of β-catenin, a key causative step in some of the most common and deadly forms of cancer, including colon carcinoma and melanoma (2). Intriguingly, β-catenin is thought to influence the metastatic potential of tumor cells by affecting chromatin remodeling (3). It is also a key component of adherens junctions that hold epithelial cells together (1). Now a report by Essers et al. on page 1181 of this issue identifies yet another role for β-catenin, providing compelling evidence that it also is a cofactor for the FOXO subfamily of winged helix transcription factors (4). FOXO family members promote mammalian cell survival by inducing cell cycle arrest and quiescence in response to oxidative stress (510). They also regulate longevity in model organisms (11). Thus, β-catenin continues to surprise biologists with its multifarious and possibly related roles in development and cancer, and apparently in cell survival and longevity as well.

This most recent β-catenin insight comes from studies of the roundworm Caenorhabditis elegans. Essers et al. astutely noticed that C. elegans mutants lacking the function of BAR-1, a β-catenin homolog, exhibit defects not only in Wnt signaling but also in dauer formation. This alternative larval stage is a temporary response to unfavorable conditions such as starvation, stress, or high population density (11). It is exited when favorable growth conditions return. The route to the dauer state has received much attention recently because mutations that promote this fate in larvae also increase the life span of adult worms (11). Because the C. elegans FOXO family member DAF-16 is required for both dauer development and normal longevity, Essers et al. asked whether BAR-1/β-catenin is required for DAF-16/FOXO function. Like mammalian FOXO family members, DAF-16 is negatively regulated by an insulin-like receptor called DAF-2. When activated, this receptor triggers a signaling cascade that keeps DAF-16 out of the nucleus. Loss of DAF-2 function thus activates DAF-16, launching the dauer fate and increased longevity (11). Essers et al. found that this scenario requires BAR-1/β-catenin. Furthermore, overexpression of BAR-1/β-catenin promotes dauer fate in a manner that depends on DAF-16/FOXO. Loss of BAR-1/β-catenin function, like loss of DAF-16/FOXO, shortens life span. These genetic studies demonstrate that BAR-1/β-catenin is required for DAF-16/FOXO function. The authors also found that BAR-1/β-catenin binds to, and presumably augments the activity of, DAF-16/FOXO. Essers et al. further show that these β-catenin functions are conserved in mammals. Expression of β-catenin and FOXO4, in a mammalian cell line that lacks endogenous β-catenin, increased the expression of transcriptional reporter genes beyond the levels induced by FOXO4 alone. Similarly, stabilization of endogenous β-catenin in mammalian cells increased FOXO4-mediated activation of reporter genes. Finally, the two mammalian proteins potentially bind each other, as they were isolated in a complex from mammalian cells.

An overview of β-catenin-dependent regulation of cell proliferation versus cell quiescence.

β-catenin interacts with FOXO transcription factors to promote exit from the cell cycle and entry into quiescence. Oxidative stress activates this function of FOXO, while insulin signaling inhibits it. β-catenin also promotes cell proliferation through its interactions with TCF transcription factors (1, 2). These two opposing functions of β-catenin may influence cancer progression and might be manipulated as a therapeutic approach.

Both DAF-16 and mammalian FOXO family members are activated in response to stress caused by highly reactive oxygen species (8, 9). This oxidative stress response results in increased expression of superoxide dismutase enzymes that eliminate reactive oxygen (10, 12). Interestingly, another consequence of FOXO activation in mammalian cells is cell cycle arrest and entry into quiescence. This nonproliferative state (57) limits damage from reactive oxygen and promotes cell survival (8, 10). Indeed, this mammalian cell cycle response may be related to dauer formation in C. elegans, as both involve physiological stasis (7). Essers et al. provide clear evidence that β-catenin is required for FOXO-mediated expression of superoxide dismutases in worms and mammalian cells, as well as for FOXO-mediated cell cycle arrest in mammalian cells. It is noteworthy that β-catenin therefore participates in two seemingly antagonistic processes: the conversion of TCF repressors into transcriptional activators to promote cell proliferation during development and tumorigenesis, and the activation of FOXO transcription factors to promote cellular dormance (see the figure).

These new findings raise intriguing questions about the involvement of β-catenin in cancer. Although it is not clear how these opposing effects influence cancer cells, Essers et al. do find endogenous β-catenin and FOXO4 in a complex in a colon carcinoma cell line. If both effects of β-catenin are operative in precancerous cell lineages, perhaps subsequent mutations in other genes negate the cell cycle arrest promoted by β-catenin's interaction with FOXO, thereby favoring tumor formation. Perhaps shifting the balance of β-catenin's interactions with TCF and FOXO could be used to favor quiescence over proliferation. Indeed, a recent study shows that FOXO transcription factors are acetylated, and that deacetylation promotes cell cycle arrest and quiescence over programmed cell death. (8). Modifiers of TCF, FOXO, or β-catenin that can shift the balance of their interactions to favor quiescence would have potential implications for cancer therapy. It is also curious that despite epidemiological evidence indicating that antioxidants lower cancer risk, these new findings suggest that activating the oxidative stress response might promote quiescence and thereby antagonize cancerous cell proliferation. Thus, the oxidative stress response may not only promote cell survival and longevity, but also may prove useful in the development of cancer therapies.

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