title: A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours.
abstract: Salmonella enterica serotype Typhimurium is a food-borne pathogen that also selectively grows in tumours and functionally decreases P-glycoprotein (P-gp), a multidrug resistance transporter. Here we report that the Salmonella type III secretion effector, SipA, is responsible for P-gp modulation through a pathway involving caspase-3. Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin). On the basis of our finding that the SipA Salmonella effector is fundamental for functionally decreasing P-gp, we engineered a nanoparticle mimic that both overcomes multidrug resistance in cancer cells and increases tumour sensitivity to conventional chemotherapeutics.
authors.affiliation: Department of Microbiology and Physiological Systems, 368 Plantation Street, Worcester, Massachusetts 01655, USA.
authors.forename: Regino
authors.initials: R
authors.lastname: Mercado-Lubo
authors.affiliation: Department of Biochemistry &Molecular Pharmacology, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Yuanwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry &Molecular Pharmacology, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Microbiology and Physiological Systems, 368 Plantation Street, Worcester, Massachusetts 01655, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Rossi
authors.affiliation: Department of Biochemistry &Molecular Pharmacology, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Biochemistry &Molecular Pharmacology, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Yekui
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Microbiology and Physiological Systems, 368 Plantation Street, Worcester, Massachusetts 01655, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Castillo
authors.affiliation: Department of Microbiology and Physiological Systems, 368 Plantation Street, Worcester, Massachusetts 01655, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Leonard
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 55 Lake Avenue North Worcester, Massachusetts 01655, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Bortell
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 55 Lake Avenue North Worcester, Massachusetts 01655, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Department of Biochemistry &Molecular Pharmacology, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Han
authors.affiliation: Department of Microbiology and Physiological Systems, 368 Plantation Street, Worcester, Massachusetts 01655, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: McCormick
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006046:Gold / Q000737:chemistry; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry*; D008840:Microfilament Proteins / Q000378:metabolism; D008954:Models, Biological; D012486:Salmonella typhimurium / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001426:Bacterial Proteins; D008840:Microfilament Proteins; C118287:SipA protein, Salmonella; D006046:Gold; D004317:Doxorubicin; D053148:Caspase 3