Cell line and drug-dependent effect of ERBB3 on cancer cell proliferation, chemosensitivity, and multidrug actions

Abstract

Cell line and drug-dependent effect of ERBB3 on cancer cell proliferation, chemosensitivity, and multidrug actions Bo Chen, Rui Mao, Hongjie Wang, Jin-Xiong She11Center for Biotechnology and Genomic Medicine, Department of Pathology; Medical College of Georgia, Augusta, GA, USAPurpose: The purpose of this study is to investigate the potential role of ERBB3 in cancer cell proliferation, chemosensitivity, and multidrug actions. ERBB3, also called Her3 (human epidermal growth factor receptor 3) in humans, is a type I transmembrane glycoprotein that is a member of the ERBB family of tyrosine kinase receptors.Methods: Cancer cell proliferation was assessed in three different cancerous cell lines (Hela, CM, and MCF7) transfected with the control or ERBB3 siRNA (small inhibitory ribonucleic acid, a short sequence of RNA which can be used to silence gene expression). A high-throughput screening (HTS) system with siRNA knockdown was developed to investigate the effect of ERBB3 on chemosensitivity and multidrug actions of United States Food and Drug Administration (FDA) approved drugs.Results: ERBB3 knockdown by siRNA significantly reduces the proliferation of Hela cells but not CM or MCF7 cells. Among the 30 tested FDA-approved anticancer drugs, all three types of cancer cells (Hela, CM, and MCF) are completely killed by nine common drugs and are completely resistant to seven common drugs. Furthermore, Hela, CM, and MCF7 cells are sensitive to six, nine, and two additional drugs, respectively, while they are partially sensitive to four, four, and one other drugs, respectively. ERBB3 knockdown enhances the sensitivity of Hela cells to seven drugs and only enhances the sensitivity of MCF cells to one drug (aclarubicin). In contrast, ERBB3 knockdown does not enhance chemosensitivity of CM cells to any tested drugs, but desensitizes these cells to erlotinib treatment. Our results also indicate that troglitazone (TRG), a peroxisome proliferator-activated receptor (PPARγ) agonist and potentially useful agent to reduce multiple drug resistance, potently inhibits the proliferation of Hela but not MCF7 or CM cells. Furthermore, TRG and other drugs have complex interactions that depend, at least partially, on the expression levels of ERBB3.Conclusion: The effect of ERBB3 on cancer cell proliferation, chemosensitivity, and multidrug actions depends on the types and combination of cancer cells and drugs. Therefore, when ERBB3 is targeted for cancer therapy, careful consideration must be paid to each patient’s individualized characteristics to select the most beneficial drug or drug combination.Keywords: ERBB family, anticancer drugs, siRNA, drug resistance, high-throughput screening, FDA-approved drugs