Bmi1 Essentially Mediates Podocalyxin-Enhanced Cisplatin Chemoresistance in Oral Tongue Squamous Cell Carcinoma

Yueying Zhou,Zhangui Tang,Fei Yan,Krishna Munnee,Leiyi Zhang,Xiaodan Fang,Hao Pan,Baisheng Wang,Roger Chammas

doi:10.1371/journal.pone.0123208

Abstract

Oral tongue squamous cell carcinoma (OTSCC) is one of the most common head and neck cancers. Innate or acquired resistance to cisplatin, a standard chemotherapy agent for OTSCC, is common in patients with OTSCC. Understanding the molecular basis for cisplatin chemoresistance in OTSCC cells may serve as a basis for identification of novel therapeutic targets. Podocalyxin (PODXL) has been found critical for malignant progression in a variety of cancers. Bmi1 has recently been found to induce cell apoptosis and cisplatin chemosensitivity in OTSCC cells. In this study, we explored the interaction between PODXL and Bmi1 in OTSCC cells, and assessed its impact on OTSCC cell chemoresistance to cisplatin. PODXL and/or Bmi1 were stably overexpressed or knocked down in SCC-4 and Tca8113 human OTSCC cells. Overexpression of PODXL in both cell lines markedly elevated the expression level of Bmi1 and the half maximal inhibitory concentration (IC50) of cisplain and reduced cisplatin-induced cell apoptosis, which was abolished by knockdown of Bmi1 or a selective focal adhesion kinase (FAK) inhibitor. On the other hand, knockdown of PODXL significantly decreased the Bmi1 expression level and cisplatin IC50 and increased cisplatin-induced cell apoptosis, which was completely reversed by overexpression of Bmi1. While overexpression and knockdown of PODXL respectively increased and decreased the FAK activity, Bmi1 showed no significant effect on the FAK activity in OTSCC cells. In addition, overexpression of PODXL markedly elevated the stability of Bmi1 mRNA, which was abolished by a selective FAK inhibitor. In conclusion, this study provides the first evidence that PODXL up-regulates the expression level of Bmi1 in OTSCC cells by increasing the stability of Bmi1 mRNA through a FAK-dependent mechanism; this effect leads to enhanced cisplatin chemoresistance in OTSCC cells. This study adds new insights into the molecular mechanisms underlying OTSCC chemoresistance.

Highlights

Oral squamous cell carcinoma is a lethal disease estimated to have a 275,000 incidence per year [1]
To investigate functional interaction between PODXL and B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) in oral tongue squamous cell carcinoma (OTSCC) cells, we stably overexpressed PODXL and Bmi1 in SCC-4 and Tca8113 human OTSCC cells by stable transfection, and on the other hand stably transduced the cells with lentiviral shRNAs to knock down PODXL and Bmi1, respectively
The results suggest that PODXL up-regulates the expression of Bmi1 in OTSCC cells at the mRNA level through a FAKdependent mechanism

Summary

Introduction

Oral squamous cell carcinoma is a lethal disease estimated to have a 275,000 incidence per year [1]. It accounts for more than 90% of all head and neck cancers and has a poor prognosis [2]. The development of oral tongue squamous cell carcinoma (OTSCC) metastasis poses clinical challenges because of the limited therapeutic options available [3]. One of the most potent platinum-based chemotherapeutic agents currently in use, is effective as a single agent or in combination with other drugs for the treatment of OTSCC [6]. Treatment with cisplatin-based chemotherapy has been found to improve the prognosis of patients with OTSCC [7]. One of the most important clinical problems for cisplatinbased OTSCC chemotherapy is the intrinsic/acquired chemoresistance to cisplatin [8]

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Conclusion