Abstract
Cancer stem cells (CSCs) are usually tolerant to chemotherapy and radiotherapy and associated with tumor relapse. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), is currently being used in clinical trials of lung cancer. However, SAHA facilitates the formation of induced pluripotent stem cells from somatic cells. We hypothesized that SAHA would mediate the CSCs properties and subsequently confer a more malignant phenotype in lung cancer. Transfected H1299 lung cancer cells, which stably expresses a triple fused reporter gene (DsRedm-Fluc-tTKsr39) under the control of CMV promoter was used to establish a xenograft mouse model. After the treatment of SAHA, H1299 cell line and tumor xenografts were sorted by fluorescence-activated cell sorting (FACS) based on aldehyde dehydrogenase (ALDH) activity. We found that SAHA could suppress the growth of xenografted H1299 tumors with decreased proportion of ALDHbr lung cancer cells indicating that SAHA may target CSCs. However, SAHA significantly enhanced the tumor initiating capacity and the expression of malignant genes such as KCNMA1, MORF4L2 and ASPM in the remaining living ALDHbr cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDHbr cells. The in vivo imaging technique may facilitate searching and characterization of CSCs.
Keywords:
ALDH activity; cancer stem cells; lung cancer; suberoylanilide hydroxamic acid (SAHA).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Aldehyde Dehydrogenase / analysis
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Animals
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Self Renewal / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Epithelial-Mesenchymal Transition / drug effects
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Flow Cytometry
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Gene Expression Regulation, Neoplastic / drug effects*
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Genes, Reporter
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Heterografts
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylase Inhibitors / therapeutic use
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Humans
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Hydroxamic Acids / pharmacology*
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Hydroxamic Acids / therapeutic use
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / biosynthesis*
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / genetics
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / enzymology
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Nerve Tissue Proteins / biosynthesis*
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Nerve Tissue Proteins / genetics
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Transfection
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Vorinostat
Substances
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ASPM protein, human
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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KCNMA1 protein, human
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
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MORF4L2 protein, human
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Neoplasm Proteins
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Nerve Tissue Proteins
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Transcription Factors
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Vorinostat
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Aldehyde Dehydrogenase