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Wnt signaling plays a critical role in development and oncogenesis. Although significant progress has been made in understanding the downstream signaling cascade of Wnt signaling, little is known regarding Wnt signaling modification of the cell death machinery. Given that numerous oncogenes transform cells by providing cell survival function, we hypothesized that Wnt signaling may inhibit apoptosis. Here, we report that cells expressing Wnt-1 were resistant to cancer therapy–mediated apoptosis. Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that Wnt-1–mediated cell survival was dependent on the activation of β-catenin/T cell factor (Tcf) transcription. Inhibition of β-catenin/Tcf transcription by expression of the dominant-negative mutant of Tcf-4 blocked Wnt-1–mediated cell survival and rendered cells sensitive to apoptotic stimuli. These results provide the first demonstration that Wnt-1 inhibits cancer therapy–mediated apoptosis and suggests that Wnt-1 may exhibit its oncogenic potential through a mechanism of anti-apoptosis.

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Summary In eukaryotic cells, the endoplasmic reticulum (ER) serves many specialized functions including biosynthesis and assembly of membrane and secretory proteins, calcium storage and production of lipids and sterols. As a plant for protein folding and posttranslational modification, the ER provides stringent quality control systems to ensure that only correctly folded proteins exit the ER and unfolded or misfolded proteins are retained and ultimately degraded. Biochemical, physiological, and pathological stimuli that interfere with ER function can disrupt ER homeostasis, impose stress to the ER, and subsequently cause accumulation of unfolded or misfolded proteins in the ER lumen. To deal with accumulation of unfolded or misfolded proteins, the cell has evolved highly specific signaling pathways collectively called the “unfolded protein response” (UPR) to restore normal ER functions. However, if the overload of unfolded or misfolded proteins in the ER is not resolved, the prolonged UPR will induce ER stress-associated programmed cell death, apoptosis, to protect the organism by removing the stressed cells. In this chapter, we summarize our current understanding of UPR-induced apoptosis and various methods to detect ER stress and apoptosis in mammalian cells.