原创力文档activating transcription factor 3 regulates in part the enhanced tumour cell cytotoxicity of the histone deacetylase inhibitor m344 and cisplatin in combination激活转录因子3调节部分增强肿瘤细胞的细胞毒性组蛋白脱乙酰酶抑制剂m344与顺铂的组合.pdfVIP
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activating transcription factor 3 regulates in part the enhanced tumour cell cytotoxicity of the histone deacetylase inhibitor m344 and cisplatin in combination激活转录因子3调节部分增强肿瘤细胞的细胞毒性组蛋白脱乙酰酶抑制剂m344与顺铂的组合
St Germain et al. Cancer Cell International 2010, 10:32
/content/10/1/32
PRIMARY RESEARCH Open Access
Activating Transcription Factor 3 regulates in part
the enhanced tumour cell cytotoxicity of the
histone deacetylase inhibitor M344 and cisplatin
in combination
Carly St Germain1,2,3, Anna O’Brien1,2,3, Jim Dimitroulakos1,2,3*
Abstract
Background: Activating Transcription Factor (ATF) 3 is a key regulator of the cellular integrated stress response
whose expression has also been correlated with pro-apoptotic activities in tumour cell models. Combination
treatments with chemotherapeutic drugs, such as cisplatin, and histone deacetylase (HDAC) inhibitors have been
demonstrated to enhance tumour cell cytotoxicity. We recently demonstrated a role for ATF3 in regulating
cisplatin-induced apoptosis and others have shown that HDAC inhibition can also induce cellular stress. In this
study, we evaluated the role of ATF3 in regulating the co-operative cytotoxicity of cisplatin in combination with an
HDAC inhibitor.
Results: The HDAC inhibitor M344 induced ATF3 expression at the protein and mRNA level in a panel of human
derived cancer cell lines as determined by Western blot and quantitative RT-PCR analyses. Combination treatment
with M344 and cisplatin lead to increased induction of ATF3 compared with cisplatin alone. Utilizing the MTT cell
viability assay, M344 treatments also enhanced the cytotoxic effects of cisplatin in these cancer cell lines. The
mechanism of ATF3 induction by M344 was found to be independent of MAPKinase pathways and dependent on
ATF4, a known regulator of ATF3 expression. ATF4 heterozygote (+/-) and knock out (-/-) mouse embryonic
fibroblast (MEF) as well as chromatin immunoprecipitation (ChIP) assays were utilized in determining the
mechanistic induction of ATF3 by M344. We also demonstrated that A
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