Ablation of Cancer Stem Cells by Therapeutic Inhibition of the MDM2-p53 Interaction in Mucoepidermoid Carcinoma.

Abstract

PURPOSE:

Unique cells characterized by multipotency, self-renewal, and high tumorigenic potential have been recently discovered in mucoepidermoid carcinomas. These cells are defined by high aldehyde dehydrogenase activity and high CD44 expression (ALDHhighCD44high) and function as cancer stem cells (CSC). It has been recently shown that p53 regulates cell differentiation, suggesting that induction of p53 by therapeutic blockade of the MDM2-p53 interaction may constitute a novel strategy to ablate CSCs. Here, we evaluated the effect of a small-molecule inhibitor of MDM2-p53 interaction (MI-773) on the fraction of CSCs in mucoepidermoid carcinoma.

EXPERIMENTAL DESIGN:

Human mucoepidermoid carcinoma cells (UM-HMC-1,-3A,-3B) were used to assess the effect of MI-773 on cell survival, cell cycle, fraction of CSCs, and expression of p53, p21, MDM2, and Bmi-1 (key regulator of self-renewal). Mice bearing xenograft tumors generated with these mucoepidermoid carcinoma cells were treated with MI-773 to determine the effect of MDM2-p53 inhibition on CSCs in vivo.

RESULTS:

MDM2 is highly expressed in human mucoepidermoid carcinoma tissues. MI-773 induced expression of p53 and its downstream targets p21 and MDM2, caused G1 cell-cycle arrest, and induced mucoepidermoid carcinoma tumor cell apoptosis in vitro. Importantly, a marked decrease in expression of Bmi-1 and in the fraction of ALDHhighCD44high (CSCs) was caused by MI-773 in vitro and in mice harboring mucoepidermoid carcinoma xenografts.

CONCLUSIONS:

Collectively, these data demonstrate that MI-773 reduces the fraction of CSCs, suggesting that patients with mucoepidermoid carcinoma might benefit from therapeutic inhibition of the MDM2-p53 interaction.

• Authors: April Andrews, Kristy Warner, Christie Rodriguez-Ramirez, Alexander T Pearson, Felipe Nör, Zhaocheng Zhang, Samuel Kerk, Aditi Kulkarni, Joseph I Helman, J Chad Brenner, Max S Wicha, Shaomeng Wang, Jacques E Nör
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 5 Pg. 1588-1600 (03 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30498096 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects, genetics)
• Carcinoma, Mucoepidermoid (drug therapy, etiology, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunohistochemistry
• Mice
• Neoplastic Stem Cells (drug effects, metabolism)
• Protein Binding
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays