Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway

**e, Qing; Yang, Zhijie; Huang, Xuanmei; Zhang, Zikang; Li, Jiangbin; Ju, Jianhua; Zhang, Hua; Ma, Junying

doi:10.1186/s13045-019-0744-3

Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway

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Published: 11 June 2019

Volume 12, article number 60, (2019)
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Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway

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Qing **e¹^na1,
Zhijie Yang²^na1,
Xuanmei Huang¹,
Zikang Zhang¹,
Jiangbin Li¹,
Jianhua Ju²,
Hua Zhang¹ &
…
Junying Ma²

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Abstract

Background

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. 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.

Methods

CCK-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.

Results

In 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.

Conclusions

This 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.

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Background

Triple-negative breast cancer (TNBC) is characterized by lack of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2), accounting for about 15–20% of all breast cancer [

Conclusions

This study found that Ilamycin C has more preferential cytotoxicity in TNBC cells than non-TNBC MCF7 and nonmalignant MCF10A cells. Further investigation revealed the mechanism that Ilamycin C can induce apoptosis and inhibit invasion and migration in TNBC by suppressing IL-6-induced STAT3 phosphorylation. This study provides the first evidence that Ilamycin C has the potential as a novel IL-6/STAT3 inhibitor for TNBC treatment in the future.

Availability of data and materials

All authors ensure that all data generated or analyzed during this study are included in this published article.

Abbreviations

TNBC:: Triple-negative breast cancer
ER:: Estrogen receptor
PR:: Progesterone receptor
HER2:: Human epidermal growth factor receptor 2
STAT3:: Signal transducer and activator of transcription-3
MOMP:: Mitochondrial outer membrane permeabilization
MMP:: Matrix metalloproteinase
EMT:: Epithelial-mesenchymal transition

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Acknowledgements

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Funding

This work was supported by the National Natural Science Foundation of China (31870046 and 81300398), the Natural Science Foundation of Guangdong Province (2016A030312014, 2018A0303130005 and 2015A03313528), the Special Support Program for Training High-Level Talents in Guangdong (201528018), and Fund of the School of Laboratory Medicine of Guangdong Medical University.

Author information

Qing **e and Zhijie Yang contributed equally to this work.

Authors and Affiliations

Department of Clinical Biochemistry, Institute of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, 523808, China
Qing **e, Xuanmei Huang, Zikang Zhang, Jiangbin Li & Hua Zhang
CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China
Zhijie Yang, Jianhua Ju & Junying Ma

Authors

Qing **e
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Zhijie Yang
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Xuanmei Huang
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Zikang Zhang
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Jiangbin Li
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Jianhua Ju
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Hua Zhang
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Junying Ma
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Contributions

JJ, HZ, and JM conceived and designed the experiments. QX and ZY performed the main experiments and analyzed the data. XH and ZZ participated in cell survival and migration assay. QX, JJ, HZ, and JM wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jianhua Ju, Hua Zhang or Junying Ma.

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Additional file 1:

Figure S1. Structure of ilamycin C. (TIF 49 kb)

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**e, Q., Yang, Z., Huang, X. et al. Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway. J Hematol Oncol 12, 60 (2019). https://doi.org/10.1186/s13045-019-0744-3

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Received: 04 March 2019
Accepted: 10 May 2019
Published: 11 June 2019
DOI: https://doi.org/10.1186/s13045-019-0744-3

Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway