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A STAT3-NFkB/DDIT3/CEBPβ axis modulates ALDH1A3 expression in chemoresistant cell subpopulations
Claudia Canino1, YuYing Luo2, Paola Marcato3
1Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.
Oncotarget
|April 15, 2015
Summary
Aldehyde dehydrogenase 1A3 (ALDH1A3) drives chemoresistance in malignant pleural mesothelioma (MPM) by suppressing DDIT3. Inhibiting STAT3-NFkB signaling reduces ALDH1A3, overcoming resistance to chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Malignant pleural mesothelioma (MPM) exhibits chemoresistance, particularly in aldehyde dehydrogenase (ALDH)-bright cell subpopulations.
- These ALDH-bright cells survive standard chemotherapy, including pemetrexed and cisplatin, contributing to treatment failure.
- Understanding the molecular mechanisms underlying ALDH-bright cell survival is crucial for developing effective MPM therapies.
Purpose of the Study:
- To investigate the role and modulation of aldehyde dehydrogenase (ALDH) expression in chemoresistant MPM cell subpopulations.
- To elucidate the molecular pathways regulating ALDH1A3 expression and its contribution to pemetrexed + cisplatin resistance.
- To explore therapeutic strategies targeting ALDH1A3 to overcome chemoresistance in MPM.
Main Methods:
- Purification and characterization of ALDH-bright MPM cell subpopulations.
- RNA interference (RNAi) to downregulate ALDH1A3 expression.
- Analysis of signaling pathways including pSTAT3(tyr705)-NFkB(p65), DDIT3 mRNA, and CEBPβ-dependent ALDH1A3 promoter activity.
- In vitro and in vivo studies using chemotherapy agents and butein, a STAT3-NFkB inhibitor.
Main Results:
- ALDH1A3 isoform was enriched in ALDH-bright MPM cells and responsible for their enzymatic activity.
- Downregulation of ALDH1A3 impaired ALDH-bright cell survival, especially after chemotherapy treatment.
- A pSTAT3(tyr705)-NFkB(p65) complex repressed DDIT3 mRNA, maintaining high ALDH1A3 promoter activity.
- Inhibition of STAT3-NFkB signaling increased DDIT3 expression, reduced ALDH1A3 promoter occupancy, and sensitized cells to chemotherapy, leading to increased apoptosis.
- Butein, a dual STAT3-NFkB inhibitor, reduced chemoresistance in vivo.
Conclusions:
- ALDH1A3 is a key driver of chemoresistance in MPM by regulating DDIT3 and CEBPβ.
- The pSTAT3(tyr705)-NFkB(p65) signaling pathway is critical for maintaining ALDH1A3 expression and chemoresistance.
- Targeting the STAT3-NFkB pathway, for instance with butein, represents a promising therapeutic strategy to enhance chemotherapy efficacy in MPM.
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