Chemical constituents from the Streptomyces morookaensis strain Sm4-1986.

Three new compounds, including 6-methoxy-3,4,5,7-tetramethylisochromane-3,8-diol (1), 3,4,5,7-tetramethylisochromane-3,6,8-triol (2), streptimidone derivative (3), along with ten known compounds (4-13) were isolated from the Streptomyces morookaensis strain Sm4-1986. Their chemical structures were established based on the information from UV, IR, NMR (1H NMR, 13C NMR, 1H-1H COSY, HSQC, HMBC, NOESY), and mass spectroscopic. Moreover, all the isolated new compounds were evaluated for antibacterial activities (S. aureus, B. cereus, S. epidermids and methicillin-resistant S. aureus) and their cytotoxicities against MCF-7, A549, Hela tumor cell lines and Marc-145 normal cell line.

Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ß1 secretion.

BACKGROUND: The communication between carcinoma associated fibroblasts (CAFs) and cancer cells facilitate tumor metastasis. In this study, we further underlying the epigenetic mechanisms of CAFs feed the cancer cells and the molecular mediators involved in these processes. METHODS: MCF-7 and MDA-MB-231 cells were treated with CAFs culture conditioned medium, respectively. Cytokine antibody array, enzyme-linked immunosorbent assay, western blotting and immunofluorescence were used to identify the key chemokines. Chromatin immunoprecipitation and luciferase reporter assay were performed to explore the transactivation of target LncRNA by CAFs. A series of in vitro assays was performed with RNAi-mediated knockdown to elucidate the function of LncRNA. An orthotopic mouse model of MDA-MB-231 was conducted to confirm the mechanism in vivo. RESULTS: Here we reported that TGF-ß1 was top one highest level of cytokine secreted by CAFs as revealed by cytokine antibody array. Paracrine TGF-ß1 was essential for CAFs induced EMT and metastasis in breast cancer cells, which is a crucial mediator of the interaction between stromal and cancer cells. CAF-CM significantly enhanced the HOTAIR expression to promote EMT, whereas treatment with small-molecule inhibitors of TGF-ß1 attenuated the activation of HOTAIR. Most importantly, SMAD2/3/4 directly bound the promoter site of HOTAIR, located between nucleotides -386 and -398, -440 and -452, suggesting that HOTAIR was a directly transcriptional target of SMAD2/3/4. Additionally, CAFs mediated EMT by targeting CDK5 signaling through H3K27 tri-methylation. Depletion of HOTAIR inhibited CAFs-induced tumor growth and lung metastasis in MDA-MB-231 orthotopic animal model. CONCLUSIONS: Our findings demonstrated that CAFs promoted the metastatic activity of breast cancer cells by activating the transcription of HOTAIR via TGF-ß1 secretion, supporting the pursuit of the TGF-ß1/HOTAIR axis as a target in breast cancer treatment.

Reprogramming carcinoma associated fibroblasts by AC1MMYR2 impedes tumor metastasis and improves chemotherapy efficacy.

Carcinoma associated fibroblasts (CAFs) produce a nutrient-rich microenvironment to fuel tumor progression and metastasis. Reactive oxygen species (ROS) levels and the inflammation pathway co-operate to transform CAFs. Therefore, elucidating the mechanism mediating the activity of CAFs might identify novel therapies. Abnormal miR-21 expression was reported to be involved in the conversion of resident fibroblasts to CAFs, yet the factor that drives transformation was poorly understood. Here, we reported that high miR-21 expression was strongly associated with lymph node metastasis in breast cancer, and the activation of the miR-21/NF-кB was required for the metastatic promoting effect of CAFs. AC1MMYR2, a small molecule inhibitor of miR-21, attenuated NF-кB activity by directly targeting VHL, thereby blocking the co-precipitation of NF-кB and ß-catenin and nuclear translocation. Taxol failed to constrain the aggressive behavior of cancer cells stimulated by CAFs, whereas AC1MMYR2 plus taxol significantly suppressed tumor migration and invasion ability. Remodeling and depolarization of F-actin, decreased levels of ß-catenin and vimentin, and increased E-cadherin were also detected in the combination therapy. Furthermore, reduced levels of FAP-α and α-SMA were observed, suggesting that AC1MMYR2 was competent to reprogram CAFs via the NF-кB/miR-21/VHL axis. Strikingly, a significant reduction of tumor growth and lung metastasis was observed in the combination treated mice. Taken together, our findings identified miR-21 as a critical mediator of metastasis in breast cancer through the tumor environment. AC1MMYR2 may be translated into the clinic and developed as a more personalized and effective neoadjuvant treatment for patients to reduce metastasis and improve the chemotherapy response.

AC1MMYR2 impairs high dose paclitaxel-induced tumor metastasis by targeting miR-21/CDK5 axis.

Paclitaxel (taxol) is a widely used chemo-drug for many solid tumors, while continual taxol treatment is revealed to stimulate tumor dissemination. We previously found that a small molecule inhibitor of miR-21, termed AC1MMYR2, had the potential to impair tumorigenesis and metastasis. The aim of this study was to investigate whether combining AC1MMYR2 with taxol could be explored as a means to limit tumor metastasis. Here we showed that abnormal activation of miR-21/CDK5 axis was associated with breast cancer lymph node metastasis, which was also contribute to high dose taxol-induced invasion and epithelial mesenchymal transition (EMT) in both breast cancer cell line MDA-MB-231 and glioblastoma cell line U87VIII. AC1MMYR2 attenuated CDK5 activity by functional targeting CDK5RAP1, CDK5 activator p39 and target p-FAK(ser732). A series of in vitro assays indicated that treatment of AC1MMYR2 combined with taxol suppressed tumor migration and invasion ability in both MDA-MB-231 and U87VIII cell. More importantly, combination therapy impaired high-dose taxol induced invadopodia, and EMT markers including ß-catenin, E-cadherin and vimentin. Strikingly, a significant reduction of lung metastasis in mice was observed in the AC1MMYR2 plus taxol treatment. Taken together, our work demonstrated that AC1MMYR2 appeared to be a promising strategy in combating taxol induced cancer metastasis by targeting miR-21/CDK5 axis, which highlighted the potential for development of therapeutic modalities for better clinic taxol application.