Abstract
BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis, and its treatment remains a challenge due to few targeted medicines and high risk of relapse, metastasis, and drug resistance. Thus, more effective drugs and new regimens for the therapy of TNBC are urgently needed. Ilamycins are a kind of cyclic peptides and produced by Streptomyces atratus and Streptomyces islandicus with effective anti-tuberculosis activity. Ilamycin C is a novel compound isolated from the deep South China Sea-derived Streptomyces atratus SCSIO ZH16 and exhibited a strong cytotoxic activity against several cancers including breast cancer cell line MCF7. However, the cytotoxic activity of Ilamycin C to TNBC cells and a detailed antitumor mechanism have not been reported.MethodsCCK-8 assays were used to examine cell viability and cytotoxic activity of Ilamycin C to TNBC, non-TNBC MCF7, and nonmalignant MCF10A cells. EdU assays and flow cytometry were performed to assess cell proliferation and cell apoptosis. Transwell migration and Matrigel invasion assays were utilized to assess the migratory and invading capacity of TNBC cells following the treatment of Ilamycin C. The expressions of proteins were detected by western blot.ResultsIn this study, we found that Ilamycin C has more preferential cytotoxicity in TNBC cells than non-TNBC MCF7 and nonmalignant MCF10A cells. Notably, our studies revealed the mechanism that Ilamycin C can induce Bax/Bcl-2-related caspase-dependent apoptosis and inhibit migration and invasion through MMP2/MMP9/vimentin/fascin in TNBC by suppressing IL-6-induced STAT3 phosphorylation.ConclusionsThis study provides the first evidence that Ilamycin C has significant implications for the potential as a novel IL-6/STAT3 inhibitor for TNBC treatment in the future.
Highlights
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis, and its treatment remains a challenge due to few targeted medicines and high risk of relapse, metastasis, and drug resistance
TNBC cells To investigate whether Ilamycin C has a better cytotoxic effect on TNBC, the cytotoxic activity of Ilamycin C was examined using a Cell Counting Kit-8 (CCK-8) assay in two TNBC cell lines (MDA-MB-231 and BT-549), non-TNBC cell line (MCF7), and normal breast epithelial cell line (MCF10A). 0.1% dimethyl sulfoxide (DMSO) was used as vehicle control
Consistent with the reported finding that activated Signal transducer and activator of transcription-3 (STAT3) was mainly found in TNBC cells [13], our results found that basal phosphorylated STAT3 (p-STAT3) and its upstream protein p-JAK2 were high in TNBC cells (MDA-MB-231 and BT-549), while weak in non-TNBC cells (MCF7) and undetectable in normal breast cells (MCF10A)
Summary
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis, and its treatment remains a challenge due to few targeted medicines and high risk of relapse, metastasis, and drug resistance. New regimens including drug development based on molecular targets or chimeric antigen receptor (CAR)-engineered T cell approach for the treatment of TNBC are urgently needed [7]. It has been found that the abnormal activity of IL6/STAT3 relates to poor prognosis and a low survival rate in TNBC; effective STAT3 inhibitors have become promising candidate drugs for treatment of it [17]. The fact that more antitumor drugs approved by the FDA and many antitumor compounds entering preclinical and clinical research are derived from marine organisms has highlighted that natural products from marine organisms have provided a constant source for new drug discovery against cancers [20]
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