title: A STAT3-NFkB/DDIT3/CEBPβ axis modulates ALDH1A3 expression in chemoresistant cell subpopulations.
abstract: Here we studied the relevance and modulation of aldehyde dehydrogenase (ALDH) expression in malignant pleural mesothelioma (MPM) chemoresistant cell subpopulations (ALDH(bright) cells), which survive pemetrexed + cisplatin treatment in vitro and in vivo. Expression of the ALDH1A3 isoform was invariably enriched in purified ALDH(bright) cells from multiple MPM cell lines and accounted for the enzymatic activity of those cells. RNAi mediated downregulation of ALDH1A3 reduced the survival of the ALDH(bright) cells at steady state and, much more, after pemetrexed + cisplatin treatment. We demonstrated, for the first time, that a pSTAT3(tyr705)-NFkB(p65) complex is required for the repression of DDIT3 mRNA and this ensures high levels of CEBPβ-dependent ALDH1A3 promoter activity. Inhibition of STAT3-NFkB activity allowed high levels of DDIT3 expression with increased formation of a DDIT3-CEBPβ complex. This reduced the occupancy of the ALDH1A3 promoter by CEBPβ, thus largely reducing the ALDH1A3 expression. Consequently, survival of ALDH(bright) cells in pemetrexed + cisplatin-treated cultures was impaired, following increased apoptosis. We show that such a mechanism is relevant in vivo and underlies the action of butein, a dual STAT3-NFkB inhibitor capable of abating the chemoresistance of mesothelioma cells in vivo. The possible broad translational relevance of the described mechanism is discussed.
authors: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.
authors: Claudia
authors: C
authors: Canino
authors: New York University School of Medicine, New York, USA.
authors: YuYing
authors: Y
authors: Luo
authors: Department of Pathology and Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Paola
authors: P
authors: Marcato
authors: Translational Oncogenomics Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.|Department of Oncology, Juravinski Cancer Center-McMaster University, Hamilton, Ontario, Canada.
authors: Giovanni
authors: G
authors: Blandino
authors: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.
authors: Harvey I
authors: HI
authors: Pass
authors: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.
authors: Mario
authors: M
authors: Cioce
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C497249:DDIT3 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051742:Transcription Factor CHOP; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)
keywords: ALDH; CEBPβ; DDIT3; NFkB; STAT3