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Abstract
Platinum-based chemotherapeutic drugs are widely used as components of combination chemotherapy in the treatment of cancer. One such drug, oxaliplatin, exerts a synergistic effect against advanced colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin. In the p53-proficient colorectal cancer cell line HCT116, oxaliplatin represses the expression of deoxyuridine triphosphatase (dUTPase), a ubiquitous pyrophosphatase that catalyzes the hydrolysis of dUTP to dUMP and inhibits dUTP-mediated cytotoxicity. However, the underlying mechanism of this activity has not been completely elucidated, and it remains unclear whether factors other than downregulation of dUTPase contribute to the synergistic effect of 5-FU and oxaliplatin. In this study, we found that oxaliplatin and dachplatin, platinum-based drugs containing the 1,2-diaminocyclohexane (DACH) carrier ligand, repressed the expression of nuclear isoform of dUTPase (DUT-N), whereas cisplatin and carboplatin did not. Oxaliplatin induced early p53 accumulation, upregulation of primary miR-34a transcript expression, and subsequent downregulation of E2F3 and E2F1. Nutlin-3a, which activates p53 nongenotoxically, had similar effects. Introduction of miR-34a mimic also repressed E2F1 and DUT-N expression, indicating that this miRNA plays a causative role. In addition to DUT-N, oxaliplatin repressed, in a p53-dependent manner, the expression of genes encoding enzymes involved in thymidylate biosynthesis. Consequently, oxaliplatin significantly decreased the level of dTTP in the dNTP pool in a p53-dependent manner. These data indicate that the DACH carrier ligand in oxaliplatin triggers signaling via the p53-miR-34a-E2F axis, leading to transcriptional regulation that ultimately results in accumulation of dUTP and reduced dTTP biosynthesis, potentially enhancing 5-FU cytotoxicity.
Highlights
Platinum-based chemotherapeutic drugs, such as cisplatin [cis-diamminedichloroplatinum (II)], carboplatin [cis-dia-Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online.Ó2015 American Association for Cancer Research.mmine(1,1-cyclobutanedicarboxylato)platinum (II)], and oxaliplatin [1,2-diaminocyclohexaneoxalatoplatinum (II)], are widely used in the treatment of various types of cancer, usually in combination with other types of drugs
We found that oxaliplatin and dachplatin, but not cisplatin or carboplatin, induced p53-dependent repression of DUT-N expression, confirming the involvement of Pt– DNA adducts containing the DACH carrier ligand in this process
We focused on three genes encoding enzymes of the thymidylate biosynthesis pathway, dihydrofolate reductase (DHFR), thymidine kinase 1 (TK1), and thymidylate synthase (TS), whose promoters have architectures similar to those of genes involved in the G1–S
Summary
Platinum-based chemotherapeutic drugs, such as cisplatin [cis-diamminedichloroplatinum (II)], carboplatin [cis-dia-. These microRNAs are induced by adriamycin in colon cancer cells in a p53dependent manner [16] and by nutlin-3a, a small-molecule activator of p53 that disrupts the p53–MDM2 interaction by binding to the hydrophobic pocket of MDM2 even in the absence of genotoxic stress [17, 18] It remains unknown whether miR-34a is involved in transcriptional regulation under oxaliplatin-induced stress. We found that oxaliplatin and dachplatin, but not cisplatin or carboplatin, induced p53-dependent repression of DUT-N expression, confirming the involvement of Pt– DNA adducts containing the DACH carrier ligand in this process. Our data indicate that DACH–Pt–DNA adducts induced by oxaliplatin effectively stabilize p53 and upregulate miR-34a, resulting in repression of gene expression driven by the transcription factors E2F3 and E2F1. The oxaliplatin-triggered suppression of thymidylate biosynthesis may increase the cytotoxicity of TS inhibitors
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