HIV Protease Inhibitors Sensitize Human Head and Neck Squamous Carcinoma Cells to Radiation by Activating Endoplasmic Reticulum Stress

Authors

Runping Liu, China Pharmaceutical University, Virginia Commonwealth University
Luyong Zhang, China Pharmaceutical University
Jing Yang, China Pharmaceutical University,Virginia Commonwealth University
Xiaoxuan Zhang, China Pharmaceutical University, Virginia Commonwealth University
Ross Mikkelsen, Virginia Commonwealth University
Shiyu Song, Virginia Commonwealth University
Huiping Zhou, Virginia Commonwealth University, McGuire Veterans Affairs Medical CenterFollow

Document Type

Article

Original Publication Date

2015

Journal/Book/Conference Title

PLOS ONE

Volume

10

Issue

5

DOI

10.1371/journal.pone.0125928

Comments

Originally published at http://doi.org/10.1371/journal.pone.0125928.

Date of Submission

November 2016

Abstract

Background

Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that HIV PIs induce cell apoptosis via activation of endoplasmic reticulum (ER) stress. The aim of this study was to examine the role of ER stress in HIV PI-induced radiosensitivity in human HNSCC.

Methodology and Principal Findings

HNSCC cell lines, SQ20B and FaDu, and the most commonly used HIV PIs, lopinavir and ritonavir (L/R), were used in this study. Clonogenic assay was used to assess the radiosensitivity. Cell viability, apoptosis and cell cycle were analyzed using Cellometer Vision CBA. The mRNA and protein levels of ER stress-related genes (eIF2α, CHOP, ATF-4, and XBP-1), as well as cell cycle related protein, cyclin D1, were detected by real time RT-PCR and Western blot analysis, respectively. The results demonstrated that L/R dose-dependently sensitized HNSCC cells to irradiation and inhibited cell growth. L/R-induced activation of ER stress was correlated to down-regulation of cyclin D1 expression and cell cycle arrest under G0/G1 phase.

Conclusion and Significance

HIV PIs sensitize HNSCC cells to radiotherapy by activation of ER stress and induction of cell cycle arrest. Our results provided evidence that HIV PIs can be potentially used in combination with radiation in the treatment of HNSCC.

Rights

Copyright: © 2015 Liu et al.

Is Part Of

VCU Microbiology and Immunology Publications