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Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide
M D Bacolod1, S M Lin, S P Johnson
1Department of Surgery, Duke University Medical Center, Durham,NC 27710, USA. mdb2005@med.cornell.edu
Abstract:
The total expression profiles of two medulloblastoma cell lines resistant to the preactivated form of cyclophosphamide (4-hydroperoxycyclophosphamide, 4-HC) were examined using the Affymetrix GeneChip U133A array. Our primary objective was to look for possible genes, other than the well-studied aldehyde dehydrogenases (ALDH) that may be involved in cyclophosphamide (CP) resistance in medulloblastomas. We present here the lists of the most highly upregulated [30 for D341 MED (4-HCR); 20 for D283 MED (4-HCR)] and downregulated [19 for D341 MED (4-HCR); 15 for D283 MED (4-HCR)] genes which may be involved in conferring CP-resistance to the two medullobalstoma cell lines. The lists of genes from the two sublines almost had no overlap, suggesting different mechanisms of CP-resistance. One of the most noteworthy upregulated gene is TAP1 [90-fold increase in D341 MED (4-HCR) relative to D341 MED]. TAP1, a protein belonging to the ABC transporter family is normally involved in major histocompatibility class I (MHC I) antigen processing. This suggests the possible role of multidrug resistance (MDR), albeit atypical (which means it does not involve the usual MDR1 and MRP glycoproteins), in medulloblastoma's CP-resistance. Apart from TAP1, a number of other genes involved in MHC1 processing were upregulated in D341 MED (4HCR). D341 MED (4-HCR) also had a 20-fold increase in the expression of the aldo-keto reductase gene, AKR1B10, which may deactivate the reactive cyclophosphamide metabolite, aldophosphamide. For D283 MED (4-HCR), the most notable increase in expression is that of ALDH1B1, a member of the aldehyde dehydrogenase (ALDH) family of proteins.
Insights
This study investigated gene expression in medulloblastoma cells resistant to cyclophosphamide (CP). Researchers identified novel genes, including TAP1 and AKR1B10, involved in CP resistance, suggesting atypical multidrug resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Medulloblastoma is a common pediatric brain tumor.
- Cyclophosphamide (CP) is a chemotherapy agent used to treat medulloblastoma.
- Mechanisms of CP resistance in medulloblastoma are not fully understood, particularly beyond aldehyde dehydrogenases (ALDH).
Purpose of the Study:
- To identify genes, beyond ALDH, involved in cyclophosphamide (CP) resistance in medulloblastoma cell lines.
- To compare gene expression profiles of two CP-resistant medulloblastoma cell lines (D341 MED and D283 MED).
- To explore potential novel mechanisms of CP resistance in medulloblastoma.
Main Methods:
- Gene expression profiling of two CP-resistant medulloblastoma cell lines (D341 MED and D283 MED) using Affymetrix GeneChip U133A arrays.
- Analysis of upregulated and downregulated genes in response to 4-hydroperoxycyclophosphamide (4-HC) treatment.
- Comparison of gene expression patterns between the two cell lines to identify distinct resistance mechanisms.
Main Results:
- Significant differences in gene expression profiles were observed between the two CP-resistant medulloblastoma cell lines, suggesting distinct resistance mechanisms.
- TAP1, a gene involved in antigen processing and belonging to the ABC transporter family, was highly upregulated (90-fold) in D341 MED (4-HCR), indicating a potential role in atypical multidrug resistance (MDR).
- Other genes involved in MHC I processing were also upregulated in D341 MED (4-HCR). The aldo-keto reductase gene AKR1B10 was upregulated (20-fold) in D341 MED (4-HCR), potentially deactivating aldophosphamide. ALDH1B1, an aldehyde dehydrogenase, was notably upregulated in D283 MED (4-HCR).
Conclusions:
- Cyclophosphamide resistance in medulloblastoma can involve diverse genetic mechanisms, not solely relying on aldehyde dehydrogenases.
- The upregulation of TAP1 suggests a role for atypical multidrug resistance pathways in medulloblastoma's response to CP.
- Further investigation into genes like TAP1, AKR1B10, and ALDH1B1 is warranted to fully elucidate CP resistance mechanisms and develop targeted therapies.
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