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Mechanisms of Action: Physiological Effects

NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast

Qiannan Liu, Xiaoxu Guo, Guanglie Jiang, Guoxiang Wu, Hao Miao, Kun Liu, Si Chen, Norihiro Sakamoto, Takayoshi Kuno, Fan Yao, Yue Fang
Qiannan Liu
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
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Xiaoxu Guo
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
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Guanglie Jiang
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
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Guoxiang Wu
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
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Hao Miao
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
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Kun Liu
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
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Si Chen
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
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Norihiro Sakamoto
cDivision of Food and Drug Evaluation Science, Kobe University Graduate School of Medicine, Kobe, Japan
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Takayoshi Kuno
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
cDivision of Food and Drug Evaluation Science, Kobe University Graduate School of Medicine, Kobe, Japan
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Fan Yao
bDepartment of Breast Surgery and Surgical Oncology, Research Unit of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
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Yue Fang
aDepartment of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
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  • ORCID record for Yue Fang
DOI: 10.1128/AAC.00079-20
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ABSTRACT

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 Ca2+ 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.

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NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast
Qiannan Liu, Xiaoxu Guo, Guanglie Jiang, Guoxiang Wu, Hao Miao, Kun Liu, Si Chen, Norihiro Sakamoto, Takayoshi Kuno, Fan Yao, Yue Fang
Antimicrobial Agents and Chemotherapy Aug 2020, 64 (9) e00079-20; DOI: 10.1128/AAC.00079-20

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NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast
Qiannan Liu, Xiaoxu Guo, Guanglie Jiang, Guoxiang Wu, Hao Miao, Kun Liu, Si Chen, Norihiro Sakamoto, Takayoshi Kuno, Fan Yao, Yue Fang
Antimicrobial Agents and Chemotherapy Aug 2020, 64 (9) e00079-20; DOI: 10.1128/AAC.00079-20
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KEYWORDS

Tamoxifen
NADPH-cytochrome P450 reductase Ccr1
cell wall integrity
fission yeast

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