title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.|Department of Vascular Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Wu
authors.affiliation: Laboratory of General Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jieyi
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shao
authors.affiliation: Department of Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Laboratory of General Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ruiming
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Vascular Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Breast Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.|Department of Vascular Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shenming
authors.initials: S
authors.lastname: Wang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; C025946:3-methyladenine; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D000225:Adenine