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Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids.

L'Espérance S, Bachvarova M, Tetu B, Mes-Masson AM, Bachvarov D - BMC Genomics (2008)

Bottom Line: However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment.Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids.Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Laval University, Québec (Québec), Canada. syles@hotmail.com

ABSTRACT

Background: Chemotherapy (CT) resistance in ovarian cancer (OC) is broad and encompasses diverse unrelated drugs, suggesting more than one mechanism of resistance. To better understand the molecular mechanisms controlling the immediate response of OC cells to CT exposure, we have performed gene expression profiling in spheroid cultures derived from six OC cell lines (OVCAR3, SKOV3, TOV-112, TOV-21, OV-90 and TOV-155), following treatment with 10,0 microM cisplatin, 2,5 microM paclitaxel or 5,0 microM topotecan for 72 hours.

Results: Exposure of OC spheroids to these CT drugs resulted in differential expression of genes associated with cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling. Genes, functionally involved in DNA repair, DNA replication and cell cycle arrest were mostly overexpressed, while genes implicated in metabolism (especially lipid metabolism), signal transduction, immune and inflammatory response, transport, transcription regulation and protein biosynthesis, were commonly suppressed following all treatments. Cisplatin and topotecan treatments triggered similar alterations in gene and pathway expression patterns, while paclitaxel action was mainly associated with induction of genes and pathways linked to cellular assembly and organization (including numerous tubulin genes), cell death and protein synthesis. The microarray data were further confirmed by pathway and network analyses.

Conclusion: Most alterations in gene expression were directly related to mechanisms of the cytotoxics actions in OC spheroids. However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment. Similarly, overexpression of different tubulin genes upon exposure to paclitaxel could represent an early compensatory effect to this drug action. Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids. Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

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Functional analysis for a dataset of differentially expressed genes (≥1.5 fold) in OC spheroids following CT drugs treatments. A. Functional analysis following all drugs (cisplatin, topotecan and paclitaxel) treatment, B. Functional analysis following cisplatin treatment. Top functions that meet a p-value cutoff of 0.05 are displayed.
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Figure 1: Functional analysis for a dataset of differentially expressed genes (≥1.5 fold) in OC spheroids following CT drugs treatments. A. Functional analysis following all drugs (cisplatin, topotecan and paclitaxel) treatment, B. Functional analysis following cisplatin treatment. Top functions that meet a p-value cutoff of 0.05 are displayed.

Mentions: Pathway and network analyses based on the 971 gene list were generated through the use of Ingenuity Pathways Analysis (IPA). The IPA analysis confirmed the major functionally related groups, found to be commonly up- or down-regulated in drugs-treated OC spheroids. Thus, pathways linked to cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling were both induced and suppressed; pathways functionally related to DNA replication, recombination and repair and cellular response to therapeutics were induced, while pathways associated with control of gene expression, metabolism, transport, immune and inflammatory response displayed suppression upon treatments with all drugs (Figure 1A).


Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids.

L'Espérance S, Bachvarova M, Tetu B, Mes-Masson AM, Bachvarov D - BMC Genomics (2008)

Functional analysis for a dataset of differentially expressed genes (≥1.5 fold) in OC spheroids following CT drugs treatments. A. Functional analysis following all drugs (cisplatin, topotecan and paclitaxel) treatment, B. Functional analysis following cisplatin treatment. Top functions that meet a p-value cutoff of 0.05 are displayed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2279123&req=5

Figure 1: Functional analysis for a dataset of differentially expressed genes (≥1.5 fold) in OC spheroids following CT drugs treatments. A. Functional analysis following all drugs (cisplatin, topotecan and paclitaxel) treatment, B. Functional analysis following cisplatin treatment. Top functions that meet a p-value cutoff of 0.05 are displayed.
Mentions: Pathway and network analyses based on the 971 gene list were generated through the use of Ingenuity Pathways Analysis (IPA). The IPA analysis confirmed the major functionally related groups, found to be commonly up- or down-regulated in drugs-treated OC spheroids. Thus, pathways linked to cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling were both induced and suppressed; pathways functionally related to DNA replication, recombination and repair and cellular response to therapeutics were induced, while pathways associated with control of gene expression, metabolism, transport, immune and inflammatory response displayed suppression upon treatments with all drugs (Figure 1A).

Bottom Line: However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment.Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids.Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Laval University, Québec (Québec), Canada. syles@hotmail.com

ABSTRACT

Background: Chemotherapy (CT) resistance in ovarian cancer (OC) is broad and encompasses diverse unrelated drugs, suggesting more than one mechanism of resistance. To better understand the molecular mechanisms controlling the immediate response of OC cells to CT exposure, we have performed gene expression profiling in spheroid cultures derived from six OC cell lines (OVCAR3, SKOV3, TOV-112, TOV-21, OV-90 and TOV-155), following treatment with 10,0 microM cisplatin, 2,5 microM paclitaxel or 5,0 microM topotecan for 72 hours.

Results: Exposure of OC spheroids to these CT drugs resulted in differential expression of genes associated with cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling. Genes, functionally involved in DNA repair, DNA replication and cell cycle arrest were mostly overexpressed, while genes implicated in metabolism (especially lipid metabolism), signal transduction, immune and inflammatory response, transport, transcription regulation and protein biosynthesis, were commonly suppressed following all treatments. Cisplatin and topotecan treatments triggered similar alterations in gene and pathway expression patterns, while paclitaxel action was mainly associated with induction of genes and pathways linked to cellular assembly and organization (including numerous tubulin genes), cell death and protein synthesis. The microarray data were further confirmed by pathway and network analyses.

Conclusion: Most alterations in gene expression were directly related to mechanisms of the cytotoxics actions in OC spheroids. However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment. Similarly, overexpression of different tubulin genes upon exposure to paclitaxel could represent an early compensatory effect to this drug action. Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids. Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

Show MeSH
Related in: MedlinePlus