A Slug‐dependent mechanism is responsible for tumor suppression of p53‐stabilizing compound CP‐31398 in p53‐mutated endometrial carcinoma

Abstract

Mutation in the tumor suppressor gene p53 is the most frequent molecular defect in endometrial carcinoma (EC). Recently, CP‐31398, a p53‐stabilizing compound, has been indicated to possess the ability to alter the expression of non‐p53 target genes in addition to p53 downstream genes in tumor cells. Herein, we explore the alternative mechanisms underlying the restoration of EC tumor suppressor function in mutant p53 by CP‐31398. A p53‐mutated EC cell was constructed in AN3CA cells with restored or partial loss of Slug using lentiviral vectors, followed by treatment with 25 μM CP‐31398. A p53‐independent mechanism of CP‐31398 was confirmed by the interaction between mouse double minute 2 homolog (MDM2) and Slug AN3CA cells treated with IWR‐1 (inhibitor of Wnt response 1). Furthermore, the AN3CA cells were treated with short hairpin RNA against Slug, Wnt‐specific activators (LiCl) or inhibitors (XAV‐939) followed by CP‐31398 treatment. Moreover, AN3CA cell proliferation and apoptosis were examined. A tumorigenicity assay was conducted in nude mice. CP‐31398 could promote the apoptosis of p53‐mutated EC cells, while Slug reversed this effect. Slug ubiquitination was found to occur via binding of Slug to MDM2 in AN3CA cells. We found that CP‐31398 increased the GSK‐3ß, p‐Slug, Puma, Wtp53, and Bax expressions whereas Wnt, Mtp‐53, Slug, Bcl‐2, and Ki‐67 expressions were decreased. However, these findings were reversed following the activation of the Wnt pathway and overexpression of Slug. Finally, the in vivo experimental evidence confirmed that CP‐31398 with depleted Slug suppressed tumor growth by downregulating the Slug. Collectively, CP‐31398‐regulated Slug downregulation represses the p53‐mutated EC via the p53/Wnt/Puma pathway.

Opposing Roles of Wild-type and Mutant p53 in the Process of Epithelial to Mesenchymal Transition

“…Mechanistically, in response to DNA-damaging agents, the transcriptional complex p300-mut-p53-NF-Y is formed on the promoter of the EFNB2 gene to facilitate its transcription ( Alam et al, 2016 ). Stabilization of otherwise mutated p53 with small molecules can contribute to Mdm2-mediated degradation of Slug and cause apoptosis of endometrial cancer cells also occurring with the participation of PUMA ( Figure 3 ) ( Liu et al, 2020 ). On the other hand, in p53-positive colorectal cancer cells that undergo the EMT program, a protein complex between Vimentin and wild type p53 is formed that prevents the translocation of p53 into the nucleus and hence inactivates its transcriptional activity.…”

miR‑29b suppresses proliferation and induces apoptosis of hepatocellular carcinoma ascites H22 cells via regulating TGF‑β1 and p53 signaling pathway

“…As a cell cycle checkpoint, p53 can recognize cells with aberrant mutation, arresting the cell cycle, inhibiting cell growth and inducing cell apoptosis ( 30 ). Several p53 mutations or deficiencies have been revealed in malignant cells, enabling cancer cells to escape and proliferate ( 15 ). TGF-β1 is a pleiotropic cytokine that has been regarded as a double-edged sword in the progression of cancer ( 20 ).…”

“…The protein p53 is a key cell division checkpoint-monitoring DNA mutant ( 14 ). The function of p53 in cancer is usually impaired or mutated, which enables abnormal cell proliferation ( 15 ). Our previous studies reported that p53 may induce apoptosis in H22 cells ( 13 , 16 ).…”

The E3 Ligases in Cervical Cancer and Endometrial Cancer

“…Treatment of CC cells with these two plant extracts has been shown to significantly reduce MDM2 expression; however, the exact biological mechanisms are still unclear [ 202 ]. In addition, another MDM2-targeting small-molecule compound, CP-31398, a synthetic styrene quinazoline, was able to down-regulate MDM2 expression and restore p53 mutant function in EC [ 205 ].…”