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

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 Seaderived 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.

Role of STAT3 signaling pathway in breast cancer

“…It has been reported earlier that STAT3 can upregulate cyclin D-1, c-myc, and bcl-2 to suppress the apoptosis of breast cancer cells, indicating a potential involvement of STAT3 in cell cycle and survival [33]. Moreover, STAT3 activated by IL-6/JAK2 pathway can inhibit Bax/Bcl-2-related caspase-dependent apoptosis [34]. However, overexpression of WW domain-containing oxidoreductase (Wwox) blocks the combination of STAT3 and IL-6R, resulting in inhibition of proliferation [35].…”

“…Many of these compounds target the IL-6/ STAT3 signaling pathway. Ilamycin C is found to induce apoptosis and inhibit migration and invasion by suppressing the IL-6/STAT3 pathway [34]. A small molecule, bazedoxifene, is a novel IL-6/GP130 inhibitor that reduces breast cancer proliferation and migration [77].…”

The roles of curcumin in regulating the tumor immunosuppressive microenvironment (Review)

“…Curcumin also downregulates the levels of TGF-β and IL-10 in Treg cells, reduces their ability to stimulated Treg cells and decreases the Treg cell infiltration in tumors (86). An increased expression level of IL-6 in triple-negative breast cancer is considered to mediate the tumor immunosuppressive microenvironment, leading to tumor vaccine therapy failure (98). Curcumin is a specific inhibitor of IL-6, and the combination of curcumin and breast cancer vaccine Listeriaat-Mage-b resulted in decreased IL-6 expression levels and increased IL-12 and IFN-γ levels, resulting in greater anti-tumor efficacy compared with using vaccine alone (99).…”

Triticum vulgare Extract Modulates Protein-Kinase B and Matrix Metalloproteinases 9 Protein Expression in BV-2 Cells: Bioactivity on Inflammatory Pathway Associated with Molecular Mechanism Wound Healing

“…The final visualization of the heat map was obtained based on the intensity of the fold-charge evaluated (Figure 3). The articles that we have been using for this part of our work covered the following topics: brain injury [25,26], inflammatory mechanism [27][28][29][30][31][32], and cancer [33][34][35][36][37]. The specifications of papers included in these analyses are reported in Table 1. 2.10.…”