A STAT3-NFkB/DDIT3/CEBPβ axis modulates ALDH1A3 expression in chemoresistant cell subpopulations
2015
// Claudia Canino 1 , YuYing Luo 2 , Paola Marcato 3 , Giovanni Blandino 4,5 , Harvey I. Pass 1 and Mario Cioce 1 1 Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA 2 New York University School of Medicine, New York, USA 3 Department of Pathology and Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia , Canada 4 Translational Oncogenomics Unit, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy 5 Department of Oncology, Juravinski Cancer Center-McMaster University, Hamilton, Ontario, Canada Correspondence to: Mario Cioce, email: // Keywords : ALDH, STAT3, NFkB, DDIT3, CEBPβ Received : November 26, 2014 Accepted : March 02, 2015 Published : March 30, 2015 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.
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