title: Sensitizing effect of juglone is mediated by down regulation of Notch1 signaling pathway in trastuzumab-resistant SKBR3 cells.
abstract: Trastuzumab (Herceptin) monoclonal antibody directed against HER2 receptor has been administered as a treatment for metastatic HER2 positive breast cancer. The problematic issue in treatment of HER2 positive breast cancer cells is commonly the induction of resistance to trastuzumab which might be due to modulation of some vital signaling elements such as Notch1 and Pin1. In this study, we were aimed to investigate whether the cross talk between pin1 and Notch1 has a role in this event. Our results indicated that the expression level of Pin1 in resistant SKBR3 cells increased by about twofold relative to sensitive SKBR3 cells. Besides, Pin1 inhibition via juglone reduced the extent of proliferation, colony formation and migration capacity of resistant SKBR3 cells. In addition, despite a feed forward loop between Notch1 and Pin1 in sensitive SKBR3 cells, inhibition of Notch1 cleavage in resistant SKBR3 cells did not affect pin1 level whereas pin1 inhibition by juglone reduced the level of Hes1, p-Akt and increased the cellular content of Numb. Therefore, we concluded that pin1 inhibition could be considered as a promising sensitizing strategy to weaken trastuzumab resistance.
authors: Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran.
authors: Soraya
authors: S
authors: Sajadimajd
authors: Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran. ryazdan@ut.ac.ir.
authors: Razieh
authors: R
authors: Yazdanparast
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000235:genetics*; D009285:Naphthoquinones / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1 / Q000235:genetics; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D008565:Membrane Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; D000068878:Trastuzumab; C113026:NUMB protein, human; C078493:HES1 protein, human; C508053:ERBB2 protein, human; C000606846:PIN1 protein, human; C005134:juglone
keywords: HER2; Juglone; Notch1; Pin1; SKBR3 cells; Trastuzumab