NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast
| Autor: | Guanglie Jiang, Guoxiang Wu, Hao Miao, Norihiro Sakamoto, Takayoshi Kuno, Fan Yao, Xiaoxu Guo, Si Chen, Kun Liu, Qiannan Liu, Yue Fang |
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| Rok vydání: | 2020 |
| Předmět: |
Antifungal Agents
Mutant Vacuole fusion Reductase medicine.disease_cause 03 medical and health sciences Cell Wall Schizosaccharomyces medicine Pharmacology (medical) Candida albicans Mechanisms of Action: Physiological Effects 030304 developmental biology NADPH-Ferrihemoprotein Reductase Pharmacology 0303 health sciences Mutation biology 030306 microbiology biology.organism_classification Calcineurin Tamoxifen Infectious Diseases Schizosaccharomyces pombe Cancer research Schizosaccharomyces pombe Proteins Intracellular |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 |
| Popis: | Invasive fungal diseases are a leading cause of mortality among immunocompromised populations. Treatment is notoriously difficult due to the limited number of antifungal drugs as well as the emergence of drug resistance. Tamoxifen (TAM), a selective estrogen receptor modulator frequently used for the treatment of breast cancer, has been found to have antifungal activities and may be a useful addition to the agents used to treat fungal infectious diseases. However, the molecular mechanisms underlying its antifungal actions remain obscure. Here, we screened for mutations that confer sensitivity to azole antifungal drugs by using the fission yeast Schizosaccharomyces pombe as a model and isolated a mutant with a mutation in cls1 (ccr1), an allele of the gene encoding the NADPH-cytochrome P450 reductase Ccr1. We found that strains with a deletion of the ccr1(+) gene exhibited hypersensitivities to various drugs, including antifungal drugs (azoles, terbinafine, micafungin), the immunosuppressor FK506, and the anticancer drugs TAM and 5-fluorouracil (5-FU). Unexpectedly, the overexpression of Ccr1 caused yeast cell resistance to TAM but not the other drugs tested here. Additionally, strains with a deletion of Ccr1 displayed pleiotropic phenotypes, including defects in cell wall integrity and vacuole fusion, enhanced calcineurin activity, as well as increased intracellular Ca(2+) levels. Overexpression of the constitutively active calcineurin suppressed the drug-sensitive phenotypes of the Δccr1 cells. Notably, TAM treatment of wild-type cells resulted in pleiotropic phenotypes, similar to those of cells lacking Ccr1. Furthermore, TAM inhibited Ccr1 NADPH-cytochrome P450 reductase activities in a dose-dependent manner. Moreover, TAM treatment also inhibited the NADPH-cytochrome P450 reductase activities of Candida albicans and resulted in defective cell wall integrity. Collectively, our findings suggest that Ccr1 is a novel target of TAM and is involved in the antifungal activity of TAM by regulating cell wall integrity in fission yeast. |
| Databáze: | OpenAIRE |
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