Dovitinib Triggers Apoptosis and Autophagic Cell Death by Targeting SHP-1/p-STAT3 Signaling in Human Breast Cancers
Journal
Journal of Oncology
Journal Volume
2019
Pages
2024648
Date Issued
2019
Author(s)
Abstract
Breast cancer is the most common cancer and the leading cause of cancer deaths in women worldwide. The rising incidence rate and female mortality make it a significant public health concern in recent years. Dovitinib is a novel multitarget receptor tyrosine kinase inhibitor, which has been enrolled in several clinical trials in different cancers. However, its antitumor efficacy has not been well determined in breast cancers. Our results demonstrated that dovitinib showed significant antitumor activity in human breast cancer cell lines with dose- and time-dependent manners. Downregulation of phosphor-(p)-STAT3 and its subsequent effectors Mcl-1 and cyclin D1 was responsible for this drug effect. Ectopic expression of STAT3 rescued the breast cancer cells from cell apoptosis induced by dovitinib. Moreover, SHP-1 inhibitor reversed the downregulation of p-STAT3 induced by dovitinib, indicating that SHP-1 mediated the STAT3 inhibition effect of dovitinib. In addition to apoptosis, we found for the first time that dovitinib also activated autophagy to promote cell death in breast cancer cells. In conclusion, dovitinib induced both apoptosis and autophagy to block the growth of breast cancer cells by regulating the SHP-1-dependent STAT3 inhibition. ? 2019 Yi-Han Chiu et al.
SDGs
Other Subjects
bafilomycin A1; beclin 1; caspase 9; cyclin D1; dovitinib; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein lc3b i; protein lc3b ii; protein mcl 1; protein tyrosine phosphatase SHP 1; sequestosome 1; STAT3 protein; survivin; unclassified drug; antineoplastic activity; apoptosis; Article; autophagy; breast cancer; breast cancer cell line; cell death; cell proliferation; cell viability; controlled study; down regulation; ectopic expression; flow cytometry; HCC1937 cell line; human; human cell; IC50; MCF-7 cell line; MDA-MB-231 cell line; MDA-MB-453 cell line; MDA-MB-468 cell line; MTT assay; protein expression; protein targeting; signal transduction; SK-BR-3 cell line; Western blotting
Type
journal article