Abstract
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(tyr 705)-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.
| Original language | English |
|---|---|
| Pages (from-to) | 12637-12653 |
| Number of pages | 17 |
| Journal | Oncotarget |
| Volume | 6 |
| Issue number | 14 |
| Publication status | Published - 2015 |
Fingerprint
Keywords
- ALDH
- CEBPβ
- DDIT3
- NFkB
- STAT3
ASJC Scopus subject areas
- Oncology
Cite this
A STAT3-NFkB/DDIT3/CEBPβ axis modulates ALDH1A3 expression in chemoresistant cell subpopulations. / Canino, Claudia; Luo, YuYing; Marcato, Paola; Blandino, Giovanni; Pass, Harvey I.; Cioce, Mario.
In: Oncotarget, Vol. 6, No. 14, 2015, p. 12637-12653.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A STAT3-NFkB/DDIT3/CEBPβ axis modulates ALDH1A3 expression in chemoresistant cell subpopulations
AU - Canino, Claudia
AU - Luo, YuYing
AU - Marcato, Paola
AU - Blandino, Giovanni
AU - Pass, Harvey I.
AU - Cioce, Mario
PY - 2015
Y1 - 2015
N2 - 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(tyr 705)-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.
AB - 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(tyr 705)-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.
KW - ALDH
KW - CEBPβ
KW - DDIT3
KW - NFkB
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=84930012600&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930012600&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:84930012600
VL - 6
SP - 12637
EP - 12653
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 14
ER -