Non-Polar Myxococcus fulvus KYC4048 Metabolites Exert Anti-Proliferative Effects via Inhibition of Wnt/ß-Catenin Signaling in MCF-7 Breast Cancer Cells.

The Wnt/ß-catenin signaling pathway is involved in breast cancer and Myxococcus fulvus KYC4048 is a myxobacterial strain that can produce a variety of bioactive secondary metabolites. Although a previous study revealed that KYC4048 metabolites exhibit anti-proliferative effects on breast cancer, the biochemical mechanism involved in their effects remains unclear. In the present study, KYC4048 metabolites were separated into polar and non-polar (ethyl acetate and n-hexane) fractions via liquid-liquid extraction. The effects of these polar and non-polar KYC4048 metabolites on the viability of breast cancer cells were then determined by MTT assay. Expression levels of Wnt/ß-catenin pathway proteins were determined by Western blot analysis. Cell cycle and apoptosis were measured via fluorescence-activated cell sorting (FACS). The results revealed that non-polar KYC4048 metabolites induced cell death of breast cancer cells and decreased expression levels of WNT2B, ß-catenin, and Wnt target genes (c-Myc and cyclin D1). Moreover, the n-hexane fraction of non-polar KYC4048 metabolites was found most effective in inducing apoptosis, necrosis, and cell cycle arrest, leading us to conclude that it can induce apoptosis of breast cancer cells through the Wnt/ß-catenin pathway. These findings provide evidence that the n-hexane fraction of non-polar KYC4048 metabolites can be developed as a potential therapeutic agent for breast cancer via inhibition of the Wnt/ß-catenin pathway.

Protection and immune modulation of activated human vaginal epithelial cells by Aurea helianthus extract.

Aurea helianthus extract is associated with various properties including anti-melanogenesis, anti-oxidation, tumorigenic suppression, and immunoregulation; however, the mechanism by which it executes the immunomodulation of human vaginal epithelial cells (HVECs) remains elusive. We established three immunological functions of the extract. First, it mediated tumorigenic suppression in HVECs. Expression of cytokeratin 8, cancer antigen-125, and vimentin was dramatically downregulated in HVECs exposed to the extract under oxidative and fungal stresses. Second, the extract activated dendritic cells and macrophages. On exposing progenitor dendritic cells to the extract, the number of CD304+ cells increased by 40%; further, under oxidative and fungal stresses, this number was approximately 1.8 and 1.3 times lower, respectively, compared to that in the stressed cells. In monocytic differentiation, the number of dendritic cells and macrophages increased 9 and 6 times, respectively, compared to that in the control. Additionally, the extract enhanced and recovered polarisation by approximately 1.5 and 2 times, respectively, than that under stressed conditions. Third, the phagocytic activity of macrophages, against HPV16, 18, and 33 peptides, was enhanced by 12-35 times compared with that under stressed conditions. Thus, A. helianthus extract is a strong stimulator of the immune system and tumorigenic suppression under stress conditions.

Effects of Myxococcus fulvus KYC4048 Metabolites on Breast Cancer Cell Death.

Using MCF7 breast cancer cells, we tested the anticancer activity of metabolites from 130 strains of myxobacteria newly isolated in South Korea. Of these, three strains whose metabolites had high anticancer activity and low cell toxicity were selected and identified by their fruiting body morphology, cell morphology, and 16S rRNA sequence. Strains KYC4030 and KYC4048 were determined to be Myxococcus fulvus, whereas strain KYC4081 was identified as Corallococcus coralloides. We found that metabolites of M. fulvus KYC4048 demonstrated no toxicity in normal cells but specifically induced cancer cell death by suppressing the expression of WNT2B. This discovery highlights the value of assessing the metabolic and biomedical potential of myxobacteria, even those that are already known but were isolated from new areas, and the possible use of metabolites from M. fulvus KYC4048 in cancer treatment.

Correlation between Sorangium cellulosum subgroups and their potential for secondary metabolite production.

Phylogenetic analysis of the groEL1 and xynB1 gene sequences from Sorangium cellulosum strains isolated in Korea previously revealed the existence of at least 5 subgroups (A-E). In the present study, we used sequence analysis of polymerase chain reaction-amplified biosynthetic genes of strains from the 5 subgroups to indicate correlations between S. cellulosum subgroups and their secondary metabolic gene categories. We detected putative biosynthetic genes for disorazol, epothilone, ambruticin, and soraphen in group A, group C, group D, and group E strains, respectively. With the exception of KYC3204, culture extracts from group A, group B, and group C strains exhibited no noticeable antimicrobial inhibitory activities. By contrast, culture extracts from group D strains inhibited the growth of Candida albicans, whereas culture extracts from group E strains inhibited the growth of C. albicans and Staphylococcus aureus. High performance liquid chromatography analysis of the culture extracts from the strains of each subgroup revealed unique peak patterns. Our findings indicate the existence of at least 5 subgroups of S. cellulosum strains, each of which has the potential to produce a unique set of secondary metabolites.

Operon required for fruiting body development in Myxococcus xanthus.

We have used mutational analysis to identify four genes, MXAN3553, MXAN3554, MXAN3555, and MXAN3556, constituting an operon that is essential for normal fruiting body development in Myxococcus xanthus. Deletion of MXAN3553, which encoded a hypothetical protein, resulted in delayed fruiting body development. MXAN3554 was predicted to encode a metallopeptidase, and its deletion caused fruiting body formation to fail. Inactivation of MXAN3555, which encoded a putative NtrC-type response regulator, resulted in delayed aggregation and a severe reduction in sporulation. Fruiting bodies also failed to develop with the deletion of MXAN3556, another gene encoding a hypothetical protein.