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Ilamycin C Induces Apoptosis and Inhibits Migration and Invasion In Xie et al. Journal of Hematology & Oncology (2019) 12:60 https://doi.org/10.1186/s13045-019-0744-3 RESEARCH Open Access Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway Qing Xie1†, Zhijie Yang2†, Xuanmei Huang1, Zikang Zhang1, Jiangbin Li1, Jianhua Ju2*, Hua Zhang1* and Junying Ma2* 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. Keywords: Ilamycin C, Triple-negative breast cancer, Apoptosis, Invasion, Migration, IL-6, STAT3 * Correspondence: [email protected]; [email protected]; [email protected] †Qing Xie and Zhijie Yang contributed equally to this work. 2CAS 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 1Department of Clinical Biochemistry, Institute of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Xie et al. Journal of Hematology & Oncology (2019) 12:60 Page 2 of 14 Background detailed antitumor mechanism are still unknown. In this Triple-negative breast cancer (TNBC) is characterized work, the cytotoxicity and function of Ilamycin C in by lack of progesterone receptor (PR), estrogen receptor TNBC cells were investigated and its antitumor mechan- (ER), and human epidermal growth factor receptor 2 ism was further explored. (HER2), accounting for about 15–20% of all breast can- cer [1]. Clinically, TNBC is more aggressive and less sen- Methods sitive to typical therapies and ultimately has a higher Compounds rate of relapse and metastasis and poorer prognosis compared with other subtypes of breast cancer [2, 3]. The structural elucidation, biosynthesis, and purification Chemotherapy is the main treatment of TNBC, but method of Ilamycin C were described in our previous chemotherapy resistance has become an inevitable prob- study [21]. The purity of Ilamycin C is 97.8% analyzed lem [4]. Lack of well-defined molecular targets makes it by HPLC (high-performance liquid chromatography) a challenge to treat and improve the 5-year survival rate analysis, and it was dissolved in dimethyl sulfoxide of patients with TNBC [5, 6]. Therefore, new regimens (DMSO) (Sigma). Doxorubicin and cisplatin were pur- including drug development based on molecular targets chased from Sigma. or chimeric antigen receptor (CAR)-engineered T cell approach for the treatment of TNBC are urgently Cell culture needed [7]. MDA-MB-231, BT-549, MCF7, and MCF10A cell lines Signal transducer and activator of transcription-3 were obtained from American Type Culture Collection (STAT3) is continually activated in many human cancers (ATCC). All these cells were cultured according to [8]. It can be directly or indirectly activated by many ele- ATCC recommendations. ments, such as growth factors (PDGFR, EGFR, and HER2), cytokines (IFN-α, IL-6), and non-receptor tyro- sine kinases (Src and Janus kinase family proteins) [9– Cell infection with lentivirus 11]. Among the Janus kinase (JAK) family, JAK2 can be The lentivirus vector was purchased from GenePharma. activated by IL-6 and further recruits and phosphory- All vectors were verified by DNA sequencing. The lates STAT3, thus functioning as an intermediary be- lentivirus-STAT3 (LV-STAT3) or lentivirus-negative con- tween IL-6 and STAT3 [10]. Studies showed that activity trol (LV-NC) was used to infect MDA-MB-231 and BT- of STAT3 is closely relevant to cancer progression in- 549. After 72 h, cells were selected using 0.6 μg/ml cluding proliferation, apoptosis, and metastasis [12–16]. puromycin-resistant culture (Sigma) for a week. Cells It has also been found that the abnormal activity of IL- were collected, and the STAT3 expression was analyzed 6/STAT3 relates to poor prognosis and a low survival by quantitative polymerase chain reaction (qRT-PCR). rate in TNBC; thus, effective STAT3 inhibitors have be- come promising candidate drugs for treatment of it [17]. Cell transfection with RNA interference Currently, marine-derived natural products have For STAT3 RNA interference (RNAi), siRNA duplexes attracted great interest for their novel structure, diverse (5′-CCAACGACCUGCAGCAAUA-3′) against STAT3 bioactivities, and new function mechanisms; therefore, it (si-STAT3) and control duplex (5′-CCUACGCCAC- has become a treasure of leading compounds for the de- CAAUUUCGU-3′) were purchased from GenePharma velopment of new drugs [18, 19]. The fact that more an- and transfected into the MDA-MB-231 and BT-549 titumor drugs approved by the FDA and many using the Lipofectamine 3000 (Invitrogen) according to antitumor compounds entering preclinical and clinical the manufacturer’s guidelines. research are derived from marine organisms has highlighted that natural products from marine organ- isms have provided a constant source for new drug dis- Cell viability and proliferation assays covery against cancers [20]. Cell viability was tested by Cell Counting Kit-8 (CCK-8, Ilamycins are a kind of cyclic peptides and produced DojinDo). Cells were seeded at 3000 cells per well in 96- by Streptomyces atratus and Streptomyces islandicus well plates in triplicate and cultured for 24 h; Ilamycin C with an effective anti-tuberculosis activity [21]. Our pre- was added for 48 h. All control groups contained 0.1% vious study found that Ilamycin C (Additional file 1: DMSO. Then, 10 μL CCK-8 was added to every well, Figure S1), a novel compound isolated from the deep and plates were incubated at 37 °C for 2–3 h. The ab- South China Sea-derived Streptomyces atratus SCSIO sorbance was detected at 450 nm in a Spectra Max 190 ZH16, exhibited a strong cytotoxic activity against sev- Enzyme standard instrument (Molecular Devices). Cell eral cancers including non-TNBC cell line MCF7 [21]. proliferation was measured with Click-iT®EdU Flow Cy- However, the cytotoxic activity to TNBC cells and tometry Assay Kits (Invitrogen). Xie et al. Journal of Hematology & Oncology (2019) 12:60 Page 3 of 14 Apoptotic assays size (Millipore) and the low side was added with 10% 2.0 × 105 cells were seeded per well in six-well plates for FBS medium. Only invasion assays need to be precoated 24 h, then treated with different concentrations of Ilamy- with Matrigel. Transwell migration and invasion assays cin C for 12 or 24 h. After this, cells were stained with were performed according to the manufacturer’s instruc- Annexin V-FITC and PI or Annexin V-APC and 7-AAD tions. The images were taken by an inverted microscope at room temperature for 15 min and then analyzed by (Olympus). flow cytometry (Becton Dickinson Company). Western blot analysis Transwell assays Cells were treated with different concentrations of Ila- After treatment with Ilamycin C for 24 h, cells (2.0 × 105 mycin C for 24 h. Total proteins were obtained after the per well) were resuspended with serum-free medium disposition of cells with RIPA lysis buffer together with and seeded on the top side of the filters with 8-μm pore protease inhibitors, phosphatase inhibitors, and PMSF Fig. 1 The cytotoxic activity of Ilamycin C in breast cancer and nonmalignant cell lines. a The percentages of cell viability with the treatment of increasing concentrations of Ilamycin C for 48 h. b The IC50 values of breast cancer and nonmalignant cell lines with the treatment of Ilamycin C, doxorubicin, and cisplatin for 48 h. Experiments were performed in triplicates. ***p < 0.001, **p < 0.01, *p < 0.05 Xie et al. Journal of Hematology & Oncology (2019) 12:60 Page 4 of 14 (Beyotime, China).
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