Data from Missense Mutant p53 Transactivates Wnt/β-Catenin Signaling in Neighboring p53-Destabilized Cells through the COX-2/PGE2 Pathway

<div>Abstract<p>Missense-type p53 mutations have shown to acquire novel oncogenic roles through a gain-of-function mechanism. However, there is intratumor heterogeneity in stabilization of mutant p53 protein, and it has not been well understood about the interaction between p53-stabilized and -destabilized cells in the same tumors. We established mouse intestinal tumor–derived organoids carrying <i>Apc</i>^Δ716, <i>Kras</i>^G12D, and <i>Tgfbr2</i>^−/− mutations with <i>Trp53</i>^R270H or <i>Trp53</i>^Null mutation (AKTP^R270H and AKTP^Null, respectively). Using these organoids, we found that the activation level of Wnt/β-catenin signaling is significantly higher in AKTP^R270H cells compared with AKTP^Null cells. Notably, Wnt activation in the AKTP^Null cells was significantly increased when co-cultured with AKTP^R270H cells. Expression analysis revealed that COX-2 is significantly upregulated in AKTP^R270H but not in AKTP^Null cells, suggesting that mutant p53 induces the COX-2/prostaglandin E2 (PGE2) pathway. Importantly, Wnt activation in co-cultured AKTP^Null cells with AKTP^R270H was significantly suppressed when treated with the inhibitor of COX-2 or PGE2 receptors EP2/EP4. Furthermore, stimulation with PGE2 increased Wnt signaling activity in AKTP^Null cells. These results indicate that the COX-2/PGE2 pathway is activated in the p53-stabilized cells in the missense-type p53-mutant cancer, and secreted PGE2 may transactivate Wnt/β-catenin signaling in neighboring p53-destabilized tumor cells in the intratumor microenvironment. Therefore, targeting stabilized mutant p53 or the COX-2/PGE2 pathway may suppress Wnt/β-catenin signaling of both mutant p53–stabilized and –destabilized cells; thus, this can be a possible preventive or therapeutic strategy.</p>Significance:<p>There is intratumor heterogeneity in the stabilization of missense mutant p53, and it has been thought that only cells with nuclear accumulation of mutant p53 have oncogenic function. However, using mouse intestinal tumor–derived organoids, we show that mutant p53–stabilized cells transactivate Wnt/β-catenin signaling in neighboring p53-destabilized cells through activating the COX-2/PGE2 pathway. These results suggest that both p53-stabilized cells and p53-destabilized cells contribute to malignant progression through interaction within the intratumor microenvironment.</p></div>