MMS induced expression changes (Drosophila)
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE57788 | GEO | 2017/02/14
SECONDARY ACCESSION(S): PRJNA248121
REPOSITORIES: GEO
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Project description:Despite the high toxicity, alkylating agents are still at the forefront of several clinical protocols used to treat cancers. In this study, we investigated the mechanisms underlying alkylation damage responses, aiming to identify novel strategies to augment alkylating therapy efficacy. In this pursuit, we compared gene expression profiles of evolutionary distant cell types (D. melanogaster Kc167 cells, mouse embryonic fibroblasts and human cancer cells) in response to the alkylating agent methyl-methanesulfonate (MMS). We found that many responses to alkylation damage are conserved across species independent on their tumor/normal phenotypes. Key amongst these observations was the protective role of NRF2-induced GSH production primarily regulating GSH pools essential for MMS detoxification but also controlling activation of unfolded protein response (UPR) needed for mounting survival responses across species. An interesting finding emerged from a non-conserved mammalian-specific induction of mitogen activated protein kinase (MAPK)-dependent inflammatory responses following alkylation, which was not directly related to cell survival but stimulated the production of a pro-inflammatory, invasive and angiogenic secretome in cancer cells. Appropriate blocking of this inflammatory component blocked the invasive phenotype and angiogenesis in vitro and facilitated a controlled tumor killing by alkylation in vivo through inhibition of alkylation-induced angiogenic response, and induction of tumor healing.
2017-02-14 | GSE57789 | GEO
Project description:Despite the high toxicity, alkylating agents are still at the forefront of several clinical protocols used to treat cancers. In this study, we investigated the mechanisms underlying alkylation damage responses, aiming to identify novel strategies to augment alkylating therapy efficacy. In this pursuit, we compared gene expression profiles of evolutionary distant cell types (D. melanogaster Kc167 cells, mouse embryonic fibroblasts and human cancer cells) in response to the alkylating agent methyl-methanesulfonate (MMS). We found that many responses to alkylation damage are conserved across species independent on their tumor/normal phenotypes. Key amongst these observations was the protective role of NRF2-induced GSH production primarily regulating GSH pools essential for MMS detoxification but also controlling activation of unfolded protein response (UPR) needed for mounting survival responses across species. An interesting finding emerged from a non-conserved mammalian-specific induction of mitogen activated protein kinase (MAPK)-dependent inflammatory responses following alkylation, which was not directly related to cell survival but stimulated the production of a pro-inflammatory, invasive and angiogenic secretome in cancer cells. Appropriate blocking of this inflammatory component blocked the invasive phenotype and angiogenesis in vitro and facilitated a controlled tumor killing by alkylation in vivo through inhibition of alkylation-induced angiogenic response, and induction of tumor healing.
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Project description:Understanding the mechanisms by which cells respond to chemotherapeutics is key to identifying means to improve therapy effiicacy while reducing systemic toxicity of these widely used classes of drugs. While determining the role of NRF2-GSH and ER stress in cells exposed to alkylating compounds such as methyl-methanesulfonate (MMS), we asked if these pathways could also be a general cell damage response relevant to other clinically used chemotherapeutics or if it is an alkylation specific response. With this intent, we performed RNA sequencing of MDA-MB231 breast cancer and U2OS osteosarcoma cells lines treated for 8 hours with a topoisomerase II inhibitor etoposide (20 µM), the antimitotic beta-tubulin-interacting drug paclitaxel (0.2 µM), doxorubicin (1 µM) and compared to MMS (40 µg/mL) treated cells. Doses represent IC50 level after 72 hours exposure. We observed that even though non-alkylating drugs, especially etoposide, caused an increase in the mRNA expression of some NRF2 and ER stress signaling markers, the number and magnitude of upregulation of genes markers in either pathway was more pronounced in alkylation treatments compared to other drugs. This indicates that alterations in NRF2 and ER stress pathways could be more likely associated with differential sensitivity to alkylating chemotherapies.
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Project description:Alkylation damage to DNA occurs when cells encounter alkylating agents in the environment or when active alkylators are generated by nitrosation of amino acids in metabolic pathways. To cope with DNA alkylation damage, cells have evolved genes that encode proteins with alkylation-specific DNA repair activities. It is notable that these repair systems are conserved from bacteria to humans. In Escherichia coli, cells exposed to a low concentration of an alkylating agent, such as N-methyl-Nâ-nitro-N-nitrosoguanidine (MNNG) or methyl methanesulfonate (MMS), show a remarkable increase in resistance to both the lethal and mutagenic effects of subsequent high-level challenge treatments with the same or other alkylating agents. This increased resistance has been known as âadaptive responseâ to alkylation damage in DNA. To date, four genes have been identified as components of this response, ada, alkA, alkB and aidB. The ada gene encodes the Ada protein, which has the dual function of a transcriptional regulator for the genes involved in the adaptive response, and a methyltransferase that demethylates two methylated bases (O6meG and O4meT) and methylphosphotriesters produced by methylating agents in the sugar phosphate backbone. The differences between the wild-type and mutant strains were characterized at transcriptome levels. In addition, the global changes in gene expressions in response to alkylating agents (MMS), in E. coli K-12 W3110 and ada mutant strains were also analyzed. The analysis of time- and strain-dependent adaptive responses revealed the regulatory and physiological characteristics of the Ada-dependent adaptive response in E. coli. In order to examine the intracellular changes that are induced by the ada gene deletion in the MMS-untreated, normal growth condition, the expression levels of genes of ada mutant cells were compared with those of wild-type cells at the mid-log growth phase (at 0.5 h sampling point). Cells were cultivated at 37oC and 250 rpm in 100 mL of Luria-Bertani (LB) medium (10 g/L tryptone, 5 g/L yeast extract, and 5 g/L NaCl) in 250-mL Erlenmeyer flasks. Transcriptome analysis were also performed for the samples (E. coli wildtype and ada mutant strains) taken at 0.5, 1.5 and 3.9 h following MMS treatment for both MMS-treated and -untreated control cultures, and the expression levels were compared.
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Project description:Alkylation damage to DNA occurs when cells encounter alkylating agents in the environment or when active alkylators are generated by nitrosation of amino acids in metabolic pathways. To cope with DNA alkylation damage, cells have evolved genes that encode proteins with alkylation-specific DNA repair activities. It is notable that these repair systems are conserved from bacteria to humans. In Escherichia coli, cells exposed to a low concentration of an alkylating agent, such as N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) or methyl methanesulfonate (MMS), show a remarkable increase in resistance to both the lethal and mutagenic effects of subsequent high-level challenge treatments with the same or other alkylating agents. This increased resistance has been known as “adaptive response” to alkylation damage in DNA. To date, four genes have been identified as components of this response, ada, alkA, alkB and aidB. The ada gene encodes the Ada protein, which has the dual function of a transcriptional regulator for the genes involved in the adaptive response, and a methyltransferase that demethylates two methylated bases (O6meG and O4meT) and methylphosphotriesters produced by methylating agents in the sugar phosphate backbone. The differences between the wild-type and mutant strains were characterized at transcriptome levels. In addition, the global changes in gene expressions in response to alkylating agents (MMS), in E. coli K-12 W3110 and ada mutant strains were also analyzed. The analysis of time- and strain-dependent adaptive responses revealed the regulatory and physiological characteristics of the Ada-dependent adaptive response in E. coli.
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