BCL-2 inhibition impairs mitochondrial function and targets oral tongue squamous cell carcinoma.

Lei Xiong,Yi Tang,Zhaoyang Liu,Jing Dai,Xiaozhou Wang

doi:10.1186/s40064-016-3310-2

Abstract

PurposeTo understand the role of Bcl-2 overexpression in oral tongue squamous cell carcinoma (OTSCC) patients and investigate the efficacy of targeting Bcl-2 in OTSCC.MethodsThe expression level of Bcl-2 on normal tongue cells and OTSCC cells were measured by real-time PCR and western blotting. The functional roles of Bcl-2 were examined by MTS, flow cytometry and xenograft cancer mouse model. Mechanism studies were performed by analyzing mitochondrial functions in a panel of OTSCC cell lines.ResultsBcl-2 is up-regulated at mRNA and protein levels in a panel of OTSCC cell lines compared to normal tongue epithelial cells (NTEC). Importantly, overexpression of Bcl-2 confers resistance of OTSCC cells to chemotherapeutic drug cisplatin treatment. Overexpression of Bcl-2 in NTEC significantly increased cell growth. In contrast, inhibition of Bcl-2 by genetic and pharmacological approaches inhibits proliferation and induces apoptosis in OTSCC cells. Mechanistically, Bcl-2 inhibitor ABT-199 impairs mitochondrial functions as shown by the decreased levels of mitochondrial membrane potential, mitochondrial respiration and ATP, and the increased levels of ROS in OTSCC cells. In addition, ABT-199 inhibits proliferation and induces apoptosis and mitochondrial dysfunctions in NTEC cells, but to a less extent than in OTSCC cells. We further show that ABT-199 augments the effects of cisplatin in eliminating OTSCC cells in in vitro tongue cancer cellular system and in vivo tongue cancer xenograft mouse model.ConclusionsInhibition of Bcl-2 effectively targets OTSCC cells through inhibiting proliferation and inducing apoptosis. Inhibition of Bcl-2 also augments the inhibitory effects of cisplatin in vitro and in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-3310-2) contains supplementary material, which is available to authorized users.

Highlights

The clinical management of the majority of the oral cancer patients are still challenge with the 5-year overall survival and disease-free survival remaining ~55 and ~60 % (Goldstein et al 2013)
BCL‐2 is activated and confers resistance to chemotherapeutic drug treatment in tongue squamous carcinoma cells To understand the roles of BCL-2 in oral tongue squamous cell carcinoma (OTSCC) cells, we investigated the expression levels of BCL-2 in multiple
Consistent with the previous studies de Vicente et al (2006) and Mallick et al (2009), we found that both mRNA and protein expression levels of BCL-2 were significantly increased in all tested OTSCC cell lines compared to normal tongue epithelial cells (NTEC) (Fig. 1a, b; Additional file 1: Figure S1)

Summary

Introduction

The clinical management of the majority of the oral cancer patients are still challenge with the 5-year overall survival and disease-free survival remaining ~55 and ~60 % (Goldstein et al 2013). Oral tongue squamous cell carcinoma (OTSCC) is a subtype of oral cancer, which is more clinically aggressive with rapid local invasion and a high recurrence rate (Tan et al 2012). OTSCC has increased incidence over the last several years and poor prognosis (Garnaes et al 2015). Several studies have been shown that the expression of Bcl-2 family proteins are associated with clinical stage, histologic grade and poor prognosis in OTSCC patients (Camisasca et al 2009; de Vicente et al 2006; Zhang et al 2012). Little is known about the functional roles of Bcl-2 in OTSCC

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Conclusion