Co-Targeting IGF-1R and Autophagy Enhances the Effects of Cell Growth Suppression and Apoptosis Induced by the IGF-1R Inhibitor NVP-AEW541 in Triple-Negative Breast Cancer Cells

• Published in: PloS one 2017-01, Vol.12 (1), p.e0169229-e0169229
• Main Authors: Wu, Weibin, Ma, Jieyi, Shao, Nan, Shi, Yawei, Liu, Ruiming, Li, Wen, Lin, Yin, Wang, Shenming
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Analysis; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Autophagy-Related Protein 7 - metabolism; BAX protein; Bcl-2 protein; Biology and Life Sciences; Breast cancer; Cancer; Cancer therapies; Care and treatment; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical compounds; Chemotherapy; Clinical trials; Female; G1 Phase Cell Cycle Checkpoints - drug effects; Humans; Immunofluorescence; Immunoglobulins; Inhibition; Inhibitors; Insulin; Insulin-like growth factor I; Insulin-like growth factors; Kinases; Laboratories; Medical prognosis; Medicine and Health Sciences; Metastasis; Phagocytosis; Pharmacology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - pharmacology; Pyrroles - pharmacology; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Research and Analysis Methods; Ribonucleic acid; RNA; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Signaling; siRNA; Substrates; Treatment outcome; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumorigenesis; Tumors; Vascular surgery; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0169229

Triple-negative breast cancer (TNBC) is the most intractable type of breast cancer, and there is a lack of effective targeted therapy. Insulin-like growth factor-1 receptor (IGF-1R) is reportedly a potential target for TNBC treatment. However, satisfying treatment outcomes in breast cancer patients have yet to be achieved with IGF-1R-targeted agents. To confirm whether inhibiting IGF-1R could induce autophagy, we detected autophagy-related proteins by western blotting and immunofluorescence staining of LC3-II. The IGF-1R inhibitor NVP-AEW541, autophagy inhibitor 3-methyladenine (3-MA) and Atg7 small interfering RNA (siRNA) were used to further investigate the effects of autophagy induced by IGF-1R inhibition in TNBC cells. The CCK8 assay, EdU assay, apoptosis and cell cycle analyses were applied to test cell function after treatment. NVP-AEW541 markedly induced autophagy in TNBC cells by increasing the levels of the autophagy-related protein Beclin-1 and the LC3-II/LC-I ratio and reducing the selective autophagy substrate p62. Joint application of 3-MA or Atg7 siRNA enhanced the cell growth inhibition and apoptosis effects of NVP-AEW541 by arresting cells at G1/G0 phase and increasing Bax expression and decreasing that of Bcl-2. Targeting IGF-1R in TNBC induces cell-protective autophagy, thereby weakening the therapeutic effect of agents directed toward IGF-1R. Our findings reveal that combined use autophagy-disrupting agents can enhance the therapeutic efficacy of IGF-1R inhibitors in TNBC cells and may provide a valuable treatment strategy for IGF-1R inhibitor-based therapies for TNBC and other IGF-1 signaling-associated tumors.