A Novel Role for BDNF-TrkB in the Regulation of Chemotherapy Resistance in Head and Neck Squamous Cell Carcinoma

Junegoo Lee,Michael E Kupferman,Tilahun Jiffar,Kaustubh Datta

doi:10.1371/journal.pone.0030246

Junegoo Lee, Michael E Kupferman + Show 2 more

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https://doi.org/10.1371/journal.pone.0030246

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Journal: PloS one	Publication Date: Jan 20, 2012
Citations: 66	License type: CC BY 4.0

Affiliation: The University of Texas MD Anderson Cancer Center

Abstract

Mechanisms of resistance for HNSCC to cisplatin (CDDP), the foundational chemotherapeutic agent in the treatment of this disease, remain poorly understood. We previously demonstrated that cisplatin resistance (CR) can be overcome by targeting Trk receptor. In the current study, we explored the potential mechanistic role of the BDNF-TrkB signaling system in the development of CDDP resistance in HNSCC. Utilizing an in vitro system of acquired CR, we confirmed a substantial up-regulation of both BDNF and TrkB at the protein and mRNA levels in CR cells, suggesting an autocrine pathway dysregulation in this system. Exogenous BDNF stimulation led to an enhanced expression of the drug-resistance and anti-apoptotic proteins MDR1 and XiAP, respectively, in a dose-dependently manner, demonstrating a key role for BDNF-TrkB signaling in modulating the response to cytotoxic agents. In addition, modulation of TrkB expression induced an enhanced sensitivity of cells to CDDP in HNSCC. Moreover, genetic suppression of TrkB resulted in changes in expression of Bim, XiAP, and MDR1 contributing to HNSCC survival. To elucidate intracellular signaling pathways responsible for mechanisms underlying BDNF/TrkB induced CDDP-resistance, we analyzed expression levels of these molecules following inhibition of Akt. Inhibition of Akt eliminated BDNF effect on MDR1 and Bim expression in OSC-19P cells as well as modulated expressions of MDR1, Bim, and XiAP in OSC-19CR cells. These results suggest BDNF/TrkB system plays critical roles in CDDP-resistance development by utilizing Akt-dependent signaling pathways.

Highlights

As the sixth most common cancer worldwide, head and neck squamous cell carcinoma (HNSCC) is responsible for 5% percent of all cancers diagnosed in the United States [1]
We established that both tropomyosin-related kinase B receptor (TrkB) and brain derived neurotrophic factor (BDNF) expression was up-regulated in OSC-19CR and HN5CR cells, compared to the parental cell lines
Phenotypic characterization of cisplatin-resistant HNSCC cell lines demonstrated an upregulation of both TrkB and its ligand, brain derived neurotrophic factor (BDNF) with a concomitant increase in cell proliferation and apoptosis

Summary

Introduction

As the sixth most common cancer worldwide, head and neck squamous cell carcinoma (HNSCC) is responsible for 5% percent of all cancers diagnosed in the United States [1]. The evolution of treatment for this disease has progressed to a greater emphasis on the use of cisplatin (CDDP)-based chemotherapy in the neoadjuvant and adjuvant settings. The clinical response to CDDP is associated with only a 10–15% improvement in localregional control of disease, and marginal improvement in overall survival [2,3,4]. These sobering results suggest that resistance to CDDP (CR) is a fundamental biological property of this disease. Understanding the mechanisms underlying CDDP resistance may provide strategic targets and promising treatments against HNSCC

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