title: Bromelain reversibly inhibits invasive properties of glioma cells.
abstract: Bromelain is an aqueous extract from pineapple stem that contains proteinases and exhibits pleiotropic therapeutic effects, i.e., antiedematous, antiinflammatory, antimetastatic, antithrombotic, and fibrinolytic activities. In this study, we tested bromelain's effects on glioma cells to assess whether bromelain could be a potential contributor to new antiinvasive strategies for gliomas. Several complementary assays demonstrated that bromelain significantly and reversibly reduced glioma cell adhesion, migration, and invasion without affecting cell viability, even after treatment periods extending over several months. Immunohistochemistry and immunoblotting experiments demonstrated that alpha3 and beta1 integrin subunits and hyaluronan receptor CD44 protein levels were reduced within 24 hours of bromelain treatment. These effects were not reflected at the RNA level because RNA profiling did not show any significant effects on gene expression. Interestingly, metabolic labelling with 35-S methionine demonstrated that de novo protein synthesis was greatly attenuated by bromelain, in a reversible manner. By using a transactivating signaling assay, we found that CRE-mediated signaling processes were suppressed. These results indicate that bromelain exerts its antiinvasive effects by proteolysis, signaling cascades, and translational attenuation.
authors.affiliation: Department of Anatomy and Cell Biology, University of Bergen, Bergen N-5009, Norway. bert.tysnes@pki.uib.no
authors.forename: B B
authors.initials: BB
authors.lastname: Tysnes
authors.forename: H R
authors.initials: HR
authors.lastname: Maurer
authors.forename: T
authors.initials: T
authors.lastname: Porwol
authors.forename: B
authors.initials: B
authors.lastname: Probst
authors.forename: R
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: F
authors.initials: F
authors.lastname: Hoover
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000196:embryology; D001932:Brain Neoplasms / Q000473:pathology*; D001963:Bromelains / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002449:Cell Aggregation; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D005910:Glioma / Q000473:pathology*; D049452:Green Fluorescent Proteins; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D039422:Integrin alpha3; D019012:Integrin beta1 / Q000032:analysis; D016023:Integrins / Q000032:analysis; D008164:Luminescent Proteins / Q000096:biosynthesis; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000032:analysis; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000166:cytology; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000166:cytology / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D018960:Hyaluronan Receptors; D039422:Integrin alpha3; D019012:Integrin beta1; D016023:Integrins; D008164:Luminescent Proteins; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D001963:Bromelains