Bacterial Effector Nanoparticles as Breast Cancer Therapeutics
| Autor: | Trudy J. Padmore, Lina Herrera Estrada, Julie A. Champion |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Programmed cell death MAP Kinase Signaling System Recombinant Fusion Proteins Pharmaceutical Science Apoptosis Breast Neoplasms Biology 03 medical and health sciences Mice 0302 clinical medicine Bacterial Proteins Drug Discovery Tumor Cells Cultured Animals Humans Secretion Cell Proliferation Glutathione Transferase Antibiotics Antineoplastic Effector Cell growth Macrophages Flow Cytometry Fusion protein Cell biology 030104 developmental biology Doxorubicin 030220 oncology & carcinogenesis Cancer research NIH 3T3 Cells Molecular Medicine Nanoparticles Female Signal transduction Signal Transduction |
| Zdroj: | Molecular pharmaceutics. 13(3) |
| ISSN: | 1543-8392 |
| Popis: | Bacterial pathogens trigger cell death by a variety of mechanisms, including injection of effector proteins. Effector proteins have great potential as anticancer agents because they efficiently subvert a variety of eukaryotic signaling pathways involved in cancer development, drug resistance, and metastasis. In breast cancer, MAPK and NFκB pathways are known to be dysregulated. YopJ, an effector from Yersinia pestis, downregulates MAPK and NFκB pathways to induce cell death in specific cell types. We expressed YopJ in Escherichia coli as a fusion protein with glutathione S-transferase (GST), forming self-assembled protein nanoparticles with diameters of 100 nm. YopJ-GST nanoparticles efficiently delivered protein to cells, replacing the need for the pathogen secretion mechanism for effector delivery to cells. These nanoparticles induced dose and time dependent death in SKBR-3 breast cancer cells. After 72 h, 97% of cells died, significantly more than with the same molar dose of doxorubicin. Treatment with sublethal doses of nanoparticles decreased cell migration in vitro and downregulated the MAPK ERK 1/2 pathway, which has been correlated to metastasis. Exposure to a panel of breast cancer cell lines showed that YopJ-GST nanoparticles are cytotoxic to different subtypes, including doxorubicin resistant cells. However, they were not cytotoxic to NIH/3T3 fibroblasts or HeLa cells. Thus, YopJ-GST nanoparticles demonstrate the potential of effector proteins as breast cancer therapeutics with selective cytotoxicity and the capacity to decrease metastatic predictive behaviors. |
| Databáze: | OpenAIRE |
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