CP‑31398 attenuates endometrial cancer cell invasion, metastasis and resistance to apoptosis by downregulating MDM2 expression

Abstract

Endometrial cancer (EC) is one of the most common malignancies of the female reproductive system, and metastasis is a major cause of mortality. In this study, we aimed to explore the role of CP-31398 in the migration, invasion and apoptosis of EC cells by its regulation of the expression of the murine double minute 2 (MDM2) gene. For this purpose, EC tissues and adjacent normal tissues were collected, and the positive expression rate of MDM2 in these tissues was assessed. Subsequently, the cellular 50% inhibitory concentration (IC50) of CP-31398 was measured. The EC RL95-2 and KLE cell lines had a higher MDM2 expression and were thus selected for use in subsequent experiments. The EC cells were then treated with CP-31398 (2 µg/ml), and were transfected with siRNA against MDM2 or an MDM2 overexpression plasmid in order to examine the effects of CP-31398 and MDM2 on EC cell activities. The expression of p53, p21, Bad, Bax, B-cell lymphoma-2 (Bcl-2), cytochrome c (Cyt-c), caspase-3, Cox-2, matrix metalloproteinase (MMP)-2 and MMP-9 was measured to further confirm the effects of CP-31398 on cell migration, invasion and apoptosis. Our results indicated that MDM2 was highly expressed in EC tissues. Notably, EC cell viability decreased with the increasing concentrations of CP-31398. The EC cells treated with CP-31398 or siRNA against MDM2 exhibited an increased apoptosis and a suppressed migration and invasion, corresponding to an increased expression of p53, p21, Bad, Bax, Cyt-c and caspase-3, as well as to a decreased expression of Bcl-2, Cox-2, MMP-2 and MMP-9. Moreover, treatment with CP-31398 and siRNA against MDM2 further enhanced these effects. Taken together, the findings of this study indicate that the CP-31398-mediated downregulation of MDM2 may suppress EC progression via its inhibitory role in EC cell migration, invasion and resistance to apoptosis. Therefore, treatment with CP-31398 may prove to be possible therapeutic strategy for EC.

Prediction of Prognosis in Patients With Endometrial Carcinoma and Immune Microenvironment Estimation Based on Ferroptosis-Related Genes

“…Nevertheless, previous research has also revealed that MDM2 facilitates ferroptosis in cells with or without p53 by altering PPARα activity (Venkatesh et al, 2020). Although MDM2 downregulation in EC tissues may inhibit the progression of EC via suppressing the migration, invasion and anti-apoptosis of EC cells (Liu et al, 2019). The effect of MDM2 expression on the prognosis of EC is still controversial.…”

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

“…Hence, this could be attributed to the promoting effects of p53 on the activation of apoptotic pathways, modulating the cell cycle, and controlling DNA repair (Said et al, 2013). Furthermore, CP‐31398 has been demonstrated to exert suppressive effects in vivo by restoring the Mtp‐53‐mediated wild‐type DNA‐binding conformation in malignancies, the mechanism of which has been validated in the context of cervical cancer (Liu, Yang, et al, 2019). Meanwhile, Doppalapudi et al (2012) confirmed that CP‐31398 can stimulate the p53‐dependent cell death pathways in cancer cells, suppressing tumor growth.…”

The E3 Ligases in Cervical Cancer and Endometrial Cancer

“…The mechanism associated with MDM2 and p53 degradation is best shown in mouse models, in which the inactivation of p53 completely rescues the embryonic mortality of MDM2 when its function is lost [ 86 ]. The prototype small molecule CP-31398, a synthetic styrene quinazoline, can inhibit EC proliferation and migration by down-regulating MDM2 expression and stabilizing p53 activity [ 87 ]. Previous studies have shown that CP-31398 blocks the migration and invasion of hepatocellular carcinoma (HCC), colorectal cancer, and PCa caused by p53 deficiency both in vitro and in vivo [ 88 , 89 , 90 ].…”