Sunitinib Induces Growth Inhibition and Apoptosis in Breast Cancer MDA‐MB‐231 Cells through FOXO3a Signaling Pathway

Abstract

Sunitinib (SUN) is a new multi‐targeted oral tyrosine kinase inhibitor that been recently approved against gastrointestinal stromal tumors and advanced renal cell carcinoma. Yet, the protective effect of SUN against breast cancer is poorly investigated. In this study, we have investigated the anti‐cancer properties of SUN against breast cancer and the possible role of Forkhead box type O (FOXO3a) transcription factor in SUN‐mediated effect using MDA‐MB‐231 cells as an in vitro model. Treatment of MDA‐MB‐231 cells with SUN caused a dose‐dependent cell growth suppression due to apoptosis as mediated by activation of caspase‐3 and p53 mRNA and protein levels using quantitative polymerase chain reaction and Western blot analyses. In addition, the percentage of cells undergoing apoptosis/necrosis determined by staining with annexinV–FITC and PI using flow cytometer was increased significantly. This inhibitory effect of SUN on MDA‐MB‐231 cell growth was associated with cell cycle arrest, downregulation of cell proliferator genes such as CyclinD1, and induction of oxidative stress markers such as heme oxygenase 1. Importantly, knockdown of FOXO3a expression using small interfering RNA (siRNA) significantly rescued MDA‐MB‐231 cells from SUN‐induced cell‐proliferative arrest, apoptosis, and oxidative stress at the mRNA and protein expression levels. In conclusion, the results clearly suggest that SUN‐induced inhibition of cell proliferation and apoptosis in MDA‐MB‐231 breast cancer cells is mediated through modulation of FOXO3a expression.