title: Inhibition of metadherin sensitizes breast cancer cells to AZD6244.
abstract: The development of systemic therapy drug resistance for breast cancer treatment is an ongoing problem, thus, so are the potential molecular mechanisms of it. AZD6244 is a novel ATP-uncompetitive inhibitor to MAP/ERK kinase (MEK) 1/2 which has been demonstrated to be potent, selective and safe in the clinical trials and previous studies. However, the precise role of resistance to AZD6244 is largely unknown. We and other groups have reported that the novel oncogene Metadherin (MTDH) is associated with multiple drug resistance, but there is no report about its role in treatment of AZD6244. Here we report that the resistance to AZD6244 can be reserved by downregulating MTDH in breast cancer cell lines. When the MTDH was downregulated, the breast cancer cells exhibited a significantly increased sensitivity to AZD6244 as measured by MTT assay. After treated with AZD6244 the MTDH-knockdown cells showed more apoptosis rate and growth inhibition. We also showed that knockdown of MTDH cannot only increase expression of FOXO3a but also activate it by promoting its translocation via MTDH/ERK1/2/FOXO3a pathway rather than MTDH/AKT/FOXO3a pathway. In conclusion knockdown MTDH can enhance the breast cancer cells sensitivity to AZD6244 via regulating the expression and activity of FOXO3a. These indicate us that MTDH is a candidate marker to predict the clinical efficacy of AZD6244 and targeting MTDH could overcome the resistance to AZD6244 in breast cancer cells.
authors.affiliation: Department of Breast Surgery, Qilu Hospital, Shandong University, School of Medicine, Shandong, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Kong
authors.forename: Meena S
authors.initials: MS
authors.lastname: Moran
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016601:RNA-Binding Proteins; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D015815:Cell Adhesion Molecules; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C483039:MTDH protein, human; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins