Abstract
The Wnt/β-catenin signaling pathway plays a major role in cell survival and proliferation, as well as in angiogenesis, migration, invasion, metastasis, and stem cell renewal in various cancer types. However, the modulation (either up- or downregulation) of this pathway can inhibit cell proliferation and apoptosis both through β-catenin-dependent and independent mechanisms, and by crosstalk with other signaling pathways in a wide range of malignant tumors. Existing studies have reported conflicting results, indicating that the Wnt signaling can have both oncogenic and tumor-suppressing roles, depending on the cellular context. This review summarizes the available information on the role of the Wnt/β-catenin pathway and its crosstalk with other signaling pathways in apoptosis induction in cancer cells and presents a modified dual-signal model for the function of β-catenin. Understanding the proapoptotic mechanisms induced by the Wnt/β-catenin pathway could open new therapeutic opportunities.
Highlights
The Wnt/β-catenin pathway is severely dysregulated in various cancer cell types [1,2,3]; its components participate in the regulation of cell survival, proliferation, epithelialmesenchymal transition, inflammation, angiogenesis, migration, invasion, and stem cell renewal [4,5,6]
These results demonstrate that the modulation of the Wnt/β-catenin pathway can induce apoptotic cell death and autophagy through different mechanisms, and that the modulation of the Wnt/β-catenin pathway in multiple glioblastoma can induce apoptotic cell death and autophagy through the regulation of AMPK, c-myc, Hippo, and the p53 signaling pathway
DHA induced caspase-3-dependent apoptosis in melanoma lines by increasing the B-cell lymphoma 2 (Bcl-2) Associated X (Bax)/Bcl-2 ratio [211]. These results clearly show that the modulation of the Wnt/β-catenin pathway can induce extrinsic and intrinsic apoptosis in melanoma cells through its ability to interact with other signaling networks involved in the regulation of cell death mechanisms [211]
Summary
The Wnt/β-catenin pathway is severely dysregulated in various cancer cell types [1,2,3]; its components participate in the regulation of cell survival, proliferation, epithelialmesenchymal transition, inflammation, angiogenesis, migration, invasion, and stem cell renewal [4,5,6]. Duffy et al showed that either hyperactivating or inhibiting the Wnt/β-catenin signaling may lower cell viability rates, via apoptosis induction when the pathway is overactivated, or by inducing cell cycle arrest and differentiation when it is inhibited in malignant melanoma, colon carcinoma, and neuroblastoma tumors [17] Those authors suggest that the Wnt/β-catenin pathway shows a bidirectional vulnerability, which could open new therapeutic approaches for these and other tumor types [17]. It has been suggested that the Wnt/β-catenin pathway can induce an overexpression of c-myc, which increases the levels of p14ARF (a Mdm inhibitor), promoting the nuclear accumulation of p53 [24] These results suggest that the initial assumption that the overexpression of the Wnt/β-catenin pathway promoted the initiation, promotion, and progression of cancer and led to a worse clinical outcome could be an oversimplification [11]. This knowledge may help us to develop more effective therapies
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