A STAT3-NFkB/DDIT3/CEBPβ axis modulates ALDH1A3 expression in chemoresistant cell subpopulations
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Claudia Canino1, YuYing Luo2, Paola Marcato3, Giovanni Blandino4,5, Harvey I. Pass1 and Mario Cioce1
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
Mario Cioce, email:
Keywords: ALDH, STAT3, NFkB, DDIT3, CEBPβ
Received: November 26, 2014 Accepted: March 02, 2015 Published: March 30, 2015
Here we studied the relevance and modulation of aldehyde dehydrogenase (ALDH) expression in malignant pleural mesothelioma (MPM) chemoresistant cell subpopulations (ALDHbright cells), which survive pemetrexed + cisplatin treatment in vitro and in vivo. Expression of the ALDH1A3 isoform was invariably enriched in purified ALDHbright 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 ALDHbright 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 ALDHbright 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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