title: N-Myc and STAT Interactor regulates autophagy and chemosensitivity in breast cancer cells.
abstract: We have previously reported that expression of NMI (N-myc and STAT interactor) is compromised in invasive breast cancers. We also demonstrated that loss of NMI expression promotes epithelial-mesenchymal-transition and results in enhanced invasive ability of breast cancer cells. Additionally we had demonstrated that restoration of NMI expression reduced breast cancer xenograft growth and downregulated Wnt and TGFβ/SMAD signaling. Here we present our observations that NMI expression drives autophagy. Our studies were promoted by our observation that NMI expressing breast cancer cells showed autophagic vacuoles and LC3 processing. Additionally, we found that NMI expression increased the cisplatin sensitivity of the breast cancer cells. Our mechanistic investigations show that NMI prompts activation of GSK3-β. This multifunctional kinase is an upstream effector of the TSC1/TSC2 complex that regulates mTOR signaling. Inhibition of GSK3-β activity in NMI expressing cells activated mTOR signaling and decreased the cells' autophagic response. Additionally we demonstrate that a key component of autophagy, DNA-damage regulated autophagy modulator 1 (DRAM1), is regulated by NMI. Our TCGA database analysis reveals concurrent expression of NMI and DRAM1 in breast cancer specimens. We present evidence that NMI sensitizes breast cancer cells to cisplatin treatment through DRAM1 dependent autophagy.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Metge
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Mitra
authors.affiliation: 1] Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA [2] Comprehensive Cancer Centre, University of Alabama at Birmingham, Birmingham, AL, USA [3] Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.affiliation: 1] Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA [2] Comprehensive Cancer Centre, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Lalita A
authors.initials: LA
authors.lastname: Shevde
authors.affiliation: 1] Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA [2] Comprehensive Cancer Centre, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Samant
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; C512709:DRAM1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C099927:NMI protein, human; D034741:RNA, Small Interfering; D004317:Doxorubicin; D000071679:Glycogen Synthase Kinase 3 beta; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D002945:Cisplatin