title: Targeting the MAP kinase pathway in astrocytoma cells using a recombinant anthrax lethal toxin as a way to inhibit cell motility and invasion.
abstract: Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Understanding and targeting cancer cell invasion is an important therapeutic approach. Cell invasion is a complex process that replies on many signaling pathways including the mitogen-activated protein (MAP) kinase (MAPK). In many cell lines, the use of MAPK-targeted drugs proved to be a potential method to inhibit cancer cell motility. In the present study, we use a recombinant anthrax lethal toxin (LeTx), which selectively inhibits the MAPK pathway, in order to target invasion. LeTx proved ineffective on cell survival in astrocytoma (as well as normal cells). However, astrocytoma cells that were treated with LeTx showed a significant decrease in cell motility as seen by wound healing as well as random 2D motility in serum. The cells also showed a decrease in invasion across a collagen matrix. The effect of LeTx on cell migration was mediated though the deregulation of Rho GTPases, which play a role in cell motility. Finally, the effect of LeTx on cell migration and Rho GTPases was mimicked by the inhibition of the MAPK pathway. In this study, we describe for the first time the effect of the LeTx on cancer cell motility and invasion not cell survival making it a potentially selective brain tumor invasion inhibitor.
authors.affiliation: Department of Natural Sciences, The Lebanese American University, Beirut 1102 2801, Lebanon.
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Dimassi
authors.affiliation: Department of Natural Sciences, The Lebanese American University, Beirut 1102 2801, Lebanon.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Salloum
authors.affiliation: Department of Natural Sciences, The Lebanese American University, Beirut 1102 2801, Lebanon.
authors.forename: Bechara
authors.initials: B
authors.lastname: Saykali
authors.affiliation: Department of Natural Sciences, The Lebanese American University, Beirut 1102 2801, Lebanon.
authors.forename: Oula
authors.initials: O
authors.lastname: Khoury
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.affiliation: Department of Natural Sciences, The Lebanese American University, Beirut 1102 2801, Lebanon.
authors.forename: Ralph
authors.initials: R
authors.lastname: Abi-Habib
authors.affiliation: Department of Natural Sciences, The Lebanese American University, Beirut 1102 2801, Lebanon.
authors.forename: Mirvat
authors.initials: M
authors.lastname: El-Sibai
mesh_terms: D000942:Antigens, Bacterial / Q000494:pharmacology*; D001254:Astrocytoma / Q000188:drug therapy / Q000378:metabolism*; D001427:Bacterial Toxins / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009361:Neoplasm Invasiveness; D011994:Recombinant Proteins / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011994:Recombinant Proteins; C030325:anthrax toxin; D020741:rho GTP-Binding Proteins