Table of Contents
ISRN Oncology
Volume 2012 (2012), Article ID 746025, 10 pages
http://dx.doi.org/10.5402/2012/746025
Research Article

Adverse Cell Culture Conditions Mimicking the Tumor Microenvironment Upregulate ABCG2 to Mediate Multidrug Resistance and a More Malignant Phenotype

School of Pharmacy, The Chinese University of Hong Kong, Hong Kong

Received 7 February 2012; Accepted 1 March 2012

Academic Editors: S. Chakrabarty, P. Clavère, N. Fujimoto, and T. T. Trangas

Copyright © 2012 Grace M. Y. Cheng and Kenneth K. W. To. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

ABCG2 is an efflux transporter commonly found to overexpress in multidrug resistant (MDR) cancer cells. It is also believed to be a survival factor for cancer stem cells to drive tumor growth. Tumor microenvironment represents an attractive new drug target because it allows complex interaction between a tumor and its surrounding normal cells, molecules, and blood vessels, which all participate in tumor progression. Hypoxia, glucose deprivation and acidosis are the hallmarks of tumor microenvironment. This study investigated the upregulation of ABCG2 by these adverse growth conditions within the tumor microenvironment. Reporter gene assay revealed that a region within the ABCG2 promoter close to the reported HIF-1α response element is responsible for ABCG2 upregulation. Increased ABCG2 efflux activity was observed under the same conditions, subsequently leading to reduced response to ABCG2 substrate anticancer drug. Importantly, glucose deprivation and hypoxia were also found to enhance the resistance level of ABCG2-overexpressing resistant cells with pre-existing genetic and epigenetic MDR mechanisms. Hypoxia was further demonstrated to cause a more malignant anchorage-independent growth phenotype in the resistant cells, which can be abolished by knocking down ABCG2. A better understanding of ABCG2 regulation by the tumor microenvironment may help design novel strategies to improve treatment outcome.