title: Bacterial Effector Nanoparticles as Breast Cancer Therapeutics.
abstract: 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.
authors.affiliation: Department of Chemical & Biomolecular Engineering, Georgia Institute of Technology , 950 Atlantic Drive NW, Atlanta, Georgia 30332, United States.
authors.forename: Lina
authors.initials: L
authors.lastname: Herrera Estrada
authors.affiliation: Department of Chemical & Biomolecular Engineering, Georgia Institute of Technology , 950 Atlantic Drive NW, Atlanta, Georgia 30332, United States.
authors.forename: Trudy J
authors.initials: TJ
authors.lastname: Padmore
authors.affiliation: Department of Chemical & Biomolecular Engineering, Georgia Institute of Technology , 950 Atlantic Drive NW, Atlanta, Georgia 30332, United States.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Champion
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001426:Bacterial Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D001426:Bacterial Proteins; D011993:Recombinant Fusion Proteins; C109227:YopP protein, Yersinia; D004317:Doxorubicin; D005982:Glutathione Transferase
keywords: ERK 1/2; YopJ; bacterial effector; breast cancer; nanoparticle