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.
Highlights
Malignant Pleural Mesothelioma (MPM) is a neoplastic disease whose challenging clinical management is characterized by silent progression, extremely low response rate to chemotherapy and poor prognosis [1,2,3]
We have recently shown that pemetrexed and cisplatin treatment of MPM cell lines and primary cultures triggered the emergence of cell subpopulations exhibiting absolute chemoresistance, mesenchymal traits and high levels of aldehyde dehydrogenase (ALDH) activity (ALDHbright cells) [4] and those properties were shared by lung cancer ALDHbright cells resistant to gefinitib and cisplatin [5]
Given that the ALDHbright MPM cells are the main subcellular population resistant to pemetrexed [4] and given the ability of butein to counteract the chemoresistance of MPM cells in vitro and in vivo [35], we tested the hypothesis that the latter compound may affect the survival of the ALDHbright cell subpopulations
Summary
Malignant Pleural Mesothelioma (MPM) is a neoplastic disease whose challenging clinical management is characterized by silent progression, extremely low response rate to chemotherapy (pemetrexed + cisplatin) and poor prognosis [1,2,3]. We have recently shown that pemetrexed and cisplatin treatment of MPM cell lines and primary cultures triggered the emergence of cell subpopulations exhibiting absolute chemoresistance, mesenchymal traits and high levels of aldehyde dehydrogenase (ALDH) activity (ALDHbright cells) [4] and those properties were shared by lung cancer ALDHbright cells resistant to gefinitib and cisplatin [5]. Enriched expression of ALDH isoforms has been observed in a conspicuous number of developmentally unrelated tumors [13,14,15,16,17]. Expression of the ALDH1A3 has been experimentally shown to modulate survival of melanoma and glioma cell subpopulations exhibiting properties of cancer stem cells [18, 19] and to promote pro-tumorigenic features in breast cancer cells [20]. ALDHs can be therapeutically relevant targets in cancer [6]
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