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CP‑31398 attenuates endometrial cancer cell invasion, metastasis and resistance to apoptosis by downregulating MDM2
Ling Liu1, Li Yang1, Hui Chang2
1Department of Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
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.
Insights
CP-31398, a compound targeting murine double minute 2 (MDM2), inhibits endometrial cancer (EC) progression by reducing cell migration and invasion while promoting apoptosis. This suggests CP-31398 as a potential therapeutic strategy for EC.
Area of Science:
- Gynecologic Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Endometrial cancer (EC) is a prevalent malignancy, with metastasis being a primary cause of mortality.
- Murine double minute 2 (MDM2) gene expression is implicated in cancer progression and is often dysregulated in EC.
- Understanding the role of MDM2 and potential therapeutic agents like CP-31398 is crucial for developing effective EC treatments.
Purpose of the Study:
- To investigate the effect of CP-31398 on endometrial cancer (EC) cell migration, invasion, and apoptosis.
- To explore the mechanism by which CP-31398 regulates the expression of the murine double minute 2 (MDM2) gene in EC cells.
- To assess the potential of CP-31398 as a therapeutic strategy for endometrial cancer.
Main Methods:
- Assessed MDM2 expression in EC tissues and adjacent normal tissues.
- Determined the 50% inhibitory concentration (IC50) of CP-31398.
- Treated EC cell lines (RL95-2 and KLE) with CP-31398, siRNA against MDM2, or an MDM2 overexpression plasmid.
- Measured the expression levels of key proteins involved in apoptosis, cell cycle regulation, and invasion (p53, p21, Bad, Bax, Bcl-2, cytochrome c, caspase-3, Cox-2, MMP-2, MMP-9).
Main Results:
- MDM2 was found to be highly expressed in EC tissues.
- CP-31398 treatment decreased EC cell viability, suppressed migration and invasion, and induced apoptosis.
- CP-31398 and MDM2 downregulation increased the expression of pro-apoptotic proteins (p53, p21, Bad, Bax, cytochrome c, caspase-3) and decreased anti-apoptotic proteins (Bcl-2) and invasion markers (Cox-2, MMP-2, MMP-9).
Conclusions:
- CP-31398 effectively suppresses endometrial cancer progression by downregulating MDM2 expression.
- The mechanism involves inhibiting EC cell migration and invasion while promoting apoptosis.
- CP-31398 demonstrates significant potential as a novel therapeutic agent for endometrial cancer.
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