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Analysis of microsatellite instability in acquired drug-resistance human tumor cell lines
Samy-Felix Picard1, Noreli Franco, Catherine Sergent
1Laboratory of Molecular Genetic, Centre Georges François Leclerc, Dijon, France.
Abstract:
Genomic instability characterized as microsatellite instability (MIN) is associated with loss of DNA mismatch repair (MMR) protein. Several studies have shown that loss of DNA MMR protein confers resistance to some interacting DNA chemotherapeutic drugs, but also that exposure of MMR-proficient cells to these drugs can result in loss of MMR protein accompanied by induction of MIN. Such associations were mainly reported for cisplatin, but scarce data are available for doxorubicin (a DNA interacting agent), and nothing is known about vinblastine (an antitubulin agent). Thus, in this study we have analyzed MIN frequency in different type of human tumor cell lines characterized by their MMR protein status and resistant to doxorubicin or to vinblastine. Relationship between MIN occurrence and drug resistance was firstly verified in cisplatin resistant cells, and showed a MIN enrichment (33%) only in the MMR-deficient cells. In order to determine whether treatment of MMR-proficient cells with doxorubicin might lead to induction of MIN, we analyzed two different MMR-proficient cell lines. Variations of MIN frequency were found with either high levels of MIN (66%) or no MIN at all (0%). Effect of vinblastine was analyzed according to the MMR status in two different MMR-proficient and -deficient cells. No major change in MIN frequency was found either in the MMR-proficient (0%) or -deficient (9%) cells. Our results demonstrate that MIN occurs only in tumor cells resistant to cisplatin or doxorubicin, thus supporting earlier findings reporting such associations only with drugs interacting with DNA. Moreover, the data show that MIN does not appear in all tumor cell lines, suggesting that induction of MIN in relation to MMR status is a complex phenomenon which does not only depend on the drug considered (interacting or not with DNA), but also on the tumor cell variant.
Insights
Microsatellite instability (MIN) is linked to DNA mismatch repair (MMR) protein loss and drug resistance. This study found MIN primarily in MMR-deficient cells resistant to DNA-interacting drugs like cisplatin and doxorubicin, not vinblastine.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Genomic instability, specifically microsatellite instability (MIN), is often associated with DNA mismatch repair (MMR) protein deficiency.
- Loss of MMR protein function can lead to resistance against certain DNA-damaging chemotherapeutic drugs.
- While the link between MIN and cisplatin resistance is established, data for doxorubicin and vinblastine are limited.
Purpose of the Study:
- To investigate the frequency of MIN in human tumor cell lines with varying MMR protein status.
- To analyze the relationship between MIN and resistance to doxorubicin (DNA-interacting) and vinblastine (antitubulin) chemotherapeutic agents.
- To compare MIN induction across different drug types and tumor cell variants based on MMR proficiency.
Main Methods:
- Assessed MIN frequency in diverse human tumor cell lines exhibiting different MMR protein statuses.
- Exposed cell lines to cisplatin, doxorubicin, and vinblastine to evaluate drug resistance and subsequent MIN induction.
- Correlated MIN occurrence with MMR deficiency and resistance profiles for each drug tested.
Main Results:
- MIN enrichment (33%) was observed exclusively in MMR-deficient cells resistant to cisplatin.
- Treatment with doxorubicin induced MIN in one MMR-proficient cell line (66%) but not in another (0%).
- Vinblastine treatment showed no significant change in MIN frequency in either MMR-proficient or MMR-deficient cells.
Conclusions:
- MIN is predominantly observed in tumor cells resistant to DNA-interacting drugs like cisplatin and doxorubicin, supporting previous findings.
- The induction of MIN is a complex phenomenon influenced by the specific drug, MMR status, and intrinsic tumor cell characteristics.
- MIN does not universally occur in all tumor cell lines upon drug exposure, highlighting the heterogeneity of this process.