Cross-Talk between p53 and Wnt Signaling in Cancer

Abstract

Targeting cancer hallmarks is a cardinal strategy to improve antineoplastic treatment. However, cross-talk between signaling pathways and key oncogenic processes frequently convey resistance to targeted therapies. The p53 and Wnt pathway play vital roles for the biology of many tumors, as they are critically involved in cancer onset and progression. Over recent decades, a high level of interaction between the two pathways has been revealed. Here, we provide a comprehensive overview of molecular interactions between the p53 and Wnt pathway discovered in cancer, including complex feedback loops and reciprocal transactivation. The mutational landscape of genes associated with p53 and Wnt signaling is described, including mutual exclusive and co-occurring genetic alterations. Finally, we summarize the functional consequences of this cross-talk for cancer phenotypes, such as invasiveness, metastasis or drug resistance, and discuss potential strategies to pharmacologically target the p53-Wnt interaction.

Keywords: APC; Wnt; beta-catenin; cancer; drug resistance; metastasis; p53.

Figure 1

Overview of the p53 and Wnt pathway. (A) Schematic overview of p53 activation, regulation and transcriptional targets. Stress stimuli such as DNA damage or oncogene activation result in the activation of specific effector proteins (ATM, ATR, DNA-PK, CHK1/2, P14ARF), which stabilize p53 through phosphorylation or by inhibition of MDM2, the main negative regulator of p53. p53 itself can increase expression of MDM2, thereby creating a negative feedback loop. Activation of p53 increases the transcriptional activity of many target genes which are involved in key cellular processes (exemplary processes with target genes are shown). (B) Schematic overview of canonical Wnt signaling. In the inactive state (left), the absence of WNT ligands results in the phosphorylation of β-catenin by the destruction complex, which comprises the scaffold protein AXIN1, APC, GSK3β and CK1α. Upon phosphorylation by GSK3β, β-catenin is ubiquitinated and targeted for proteasomal degradation. Canonical Wnt signaling is activated upon binding of secreted WNT ligands to FZD receptors and LRP co-receptors (right). Plasma membrane levels of FZD and LRP receptors are regulated by secreted Wnt antagonist, such as DKK, or by the R-spondin/RNF43/ZNRF3 module. Upon binding of WNT ligands, LRP receptors are phosphorylated by CK1α and GSK3β, which leads to the activation of Dishevelled (DVL) proteins, thereby inactivating the destruction complex. As a consequence, β-catenin is stabilized, translocates to the nucleus and forms an active complex with LEF (lymphoid enhancer factor) and TCF (T-cell factor) transcription factors and co-activators such as BCL9, leading to the transcriptional activation of multiple target genes.

Figure 2

Mutational status of frequently mutated genes of the Wnt- and p53 pathways in different cancer entities. (A) Frequencies of mutations in Wnt and p53 pathway related genes in selected cancer entities. Percentage of samples with somatic mutations for the respective gene in the selected tissue type is shown. (B) Examples for mutual exclusive and co-occurring mutations in Wnt and p53 pathway associated genes. For Venn diagrams, only samples which were tested for mutations in both of the indicated genes were included. For this subset, the percentage of samples with mutations of either one or both genes were calculated. Tumor genome sequencing data were obtained from the COSMIC database [114].

Figure 3

Molecular interactions between p53 and Wnt signaling in cancer. (A) Effects of Wnt pathway components on p53 function. These include β-catenin-dependent upregulation of P14ARF, an inhibitor of MDM2, the main negative regulator of p53. Other interactions include the modulation of p53 function by direct interaction with GSK3β, Wnt-dependent repression of p53 transcription via miR-52, and stabilization of p53 by WNT5A. Interacting Wnt pathway components are colored in red. (B,C) Biological effects of wild-type (blue symbol) and mutant p53 on different Wnt pathway components (colored in red). Inhibitory (B) and activating (C) interactions are shown. Arrows indicate activation and T-shaped arrow heads indicate inhibitory interactions. The main inhibitory effects of p53 on Wnt signaling include GSK3β and SIAH1-dependent ubiquitination of β-catenin, miRNA and lncRNA-mediated repression of Wnt target genes, and induction of secreted Wnt antagonists such as DKK1 (B). p53 stimulates Wnt signaling by increasing the expression of different WNT ligands and Fzd receptors (C).

Figure 4

Cancer phenotypes that are regulated by the interaction of Wnt signaling and p53. Cancer phenotypes that depend on alterations of the Wnt and p53 pathways are shown. Tumor entities in which phenotypic effects of p53-Wnt cross-talk were detected are listed.