Antitumor Activity of Pulvomycin via Targeting Activated-STAT3 Signaling in Docetaxel-Resistant Triple-Negative Breast Cancer Cells

被引:19
作者
Byun, Woong Sub [1 ]
Bae, Eun Seo [1 ]
Cui, Jinsheng [1 ]
Park, Hyen Joo [1 ]
Oh, Dong-Chan [1 ]
Lee, Sang Kook [1 ]
机构
[1] Seoul Natl Univ, Nat Prod Res Inst, Coll Pharm, Seoul 08826, South Korea
基金
新加坡国家研究基金会;
关键词
signal transducer and activator of transcription 3; triple-negative breast cancer; resistance; metastasis; docetaxel; pulvomycin; DRUG-RESISTANCE; TUMOR-GROWTH; STAT3; ACTIVATION; DIFFERENTIATION; COMBINATION; INHIBITION; PACLITAXEL; APOPTOSIS; TAXANES;
D O I
10.3390/biomedicines9040436
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Although docetaxel-based regimens are common and effective for early-stage triple-negative breast cancer (TNBC) treatment, acquired drug resistance frequently occurs. Therefore, a novel therapeutic strategy for docetaxel-resistant TNBC is urgently required. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the tumorigenesis and metastasis of numerous cancers, and STAT3 signaling is aberrantly activated in TNBC cells. In this study, a docetaxel-resistant TNBC cell line (MDA-MB-231-DTR) was established, and mechanisms for the antitumor activity of pulvomycin, a novel STAT3 inhibitor isolated from marine-derived actinomycete, were investigated. Levels of activated STAT3 (p-STAT3 (Y705)) increased in docetaxel-resistant cells, and knockdown of STAT3 recovered the sensitivity to docetaxel in MDA-MB-231-DTR cells. Pulvomycin effectively inhibited the proliferation of both cell lines. In addition, pulvomycin suppressed the activation of STAT3 and subsequently induced G(0)/G(1) cell cycle arrest and apoptosis. Pulvomycin also significantly inhibited the invasion and migration of MDA-MB-231-DTR cells through the modulation of epithelial-mesenchymal transition markers. In an MDA-MB-231-DTR-bearing xenograft mouse model, the combination of pulvomycin and docetaxel effectively inhibited tumor growth through STAT3 regulation. Thus, our findings demonstrate that the combination of docetaxel and STAT3 inhibitors is an effective strategy for overcoming docetaxel resistance in TNBC.
引用
收藏
页数:15
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