Lipophilic statins antagonistically alter the major epithelial-to-mesenchymal transition signaling pathways in breast cancer stem-like cells via inhibition of the mevalonate pathway.

Resistance to therapies, recurrence, and metastasis remain challenging issues for breast cancer patients, particularly for triple-negative and breast cancer stem cells. The activation of the epithelial-to-mesenchymal transition (EMT) plays an indispensable role in the poor prognosis of those types. The accumulating proofs indicated that the mevalonate pathway crucially mediates a poor prognosis. Here, the effects of lipophilic 3-hydroxy-3-methyl-glutaryl-coenzyme A inhibitors, atorvastatin, lovastatin, and simvastatin, were investigated on expression and function of a selected profile of EMT-related genes in breast cancer stem-like cells. A nontoxic dose of statins (5 µM for 4 days) significantly (P < 0.05 and >2-fold change) altered expression of 50 of 71 studied genes with a shared cluster of 37 genes that are coding chief operator of signaling pathways in Hippo, Notch, Wnt, proliferation, invasion, angiogenesis, and cell death. They also significantly decreased the levels of Yap/Taz proteins and shifted the expression of vimentin/E-cadherin in favor of induction of differentiation. Statins significantly chemosensitized the treated cells to doxorubicin and also reduced in vitro migration of the cells. Whereas lovastatin and simvastatin significantly decreased the expression of CD44, atorvastatin drastically increased CD24 and caused more wide-ranging impacts. In summary, the statins hold back the process of EMT by the antagonizing of EMT-promoting pathways. High degree of overlapping findings is supportive of the central role of the mevalonate pathway in cancer stem-like cells, but further studies are required to find the optimized chemical structure for the maximum abrogation of orchestrated EMT pathways.

Intracellular production of IFN-alpha 2b in Lactococcus lactis.

Human interferon alpha (IFN-α) was expressed in two strains of Lactococcus lactis by aid of two promoters (P32 and Pnis) giving rise to two recombinant strains: MG:IFN and NZ:IFN, respectively. The expression of IFN was confirmed by ELISA and western blotting. Highest production was achieved using glucose for growth of both recombinant strains with nisin, used for induction of the recombinant strain with Pnis promoter, at 30 ng/ml. The optimum time for MG:IFN was 9 h and for NZ:IFN was 4.5 h. The highest productions by MG:IFN and NZ:IFN were 1.9 and 2.4 µg IFN/l, respectively. Both of the expressed IFNs showed bioactivities of 1.9 × 10(6) IU/mg that were acceptable for further clinical studies.