Sensitivity of colorectal cancer cells to the recombinant Anthrax lethal toxin and the Urokinase-activated Anthrax lethal toxin. (c2014)

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dc.contributor.author Kasbo, Zein Jean
dc.date.accessioned 2015-02-26T07:18:28Z
dc.date.available 2015-02-26T07:18:28Z
dc.date.issued 2015-02-26
dc.date.submitted 2014-07-22
dc.identifier.uri http://hdl.handle.net/10725/1971
dc.description Includes bibliographical references (leaves 50-53). en_US
dc.description.abstract In this study, we attempt to simultaneously target the major hallmarks of colorectal cancer (CRC), the MAPK pathway and the urokinase plasminogen activator system using a dual-selective, Urokinase-activated, recombinant anthrax lethal toxin (PrAgU2/LF). Colorectal cancer is the third most common cancer type in the world, and the second leading cause of death in the United States according to the American cancer society. Therefore, the need for alternative approaches is essential in order to overcome the difficulties faced with traditional therapies. PrAgU2/LF is composed of 2 components the binding moiety PrAgU2 and the catalytic moiety LF. PrAgU2 was obtained by replacing the furin cleavage sequence on PrAg with a urokinase- specific cleavage sequence. LF is a metalloprotease that cleaves and inactivates MEKs and hence inhibits the MAPK pathway. We assessed the cytotoxic effects and mechanisms of PrAgU2/LF on a panel of 9 human colorectal cancer cell lines.PrAg/LF, PrAg/FP59 and PrAgU2/FP59 were used as controls for the different components of this system. PrAgU2/LF was not significantly cytotoxic to any of the cell lines tested, which were also resistant to PrAg/LF, indicating resistance to the inhibition of the MAPK pathway. This was further confirmed by resistance of these cells to the MEK1/2 inhibitor U0126. Notably, the majority of cell lines showed high levels of phospho-MEK1/2 but, surprisingly, no phospho-ERK1/2. Furthermore, targeting both the MAPK pathway and the PI3-kinase/Akt pathway also failed to induce cytotoxicity in colon cancer cell lines. In order to assess the possibility of targeting the uPA/uPAR system alone, we determined expression levels of uPAR and tested the sensitivity of CRC cells to PrAgU2/FP59, a urokinase activated, MAPK-independent version of the toxin. The vast majority of cell lines tested expressed uPAR and were sensitive to PrAgU2/FP59, indicating the possibility for targeting this protease system in CRC. en_US
dc.language.iso en en_US
dc.subject Colon (Anatomy) -- Cancer -- Treatment en_US
dc.subject Rectum -- Cancer -- Treatment en_US
dc.subject Bacillus anthracis -- Toxicology en_US
dc.subject Anthrax en_US
dc.subject Urokinase -- Therapeutic use en_US
dc.subject Lebanese American University -- Dissertations en_US
dc.subject Dissertations, Academic en_US
dc.title Sensitivity of colorectal cancer cells to the recombinant Anthrax lethal toxin and the Urokinase-activated Anthrax lethal toxin. (c2014) en_US
dc.type Thesis en_US
dc.term.submitted Summer I en_US
dc.author.degree MS in Molecular Biology en_US
dc.author.school Arts and Sciences en_US
dc.author.idnumber 201205836 en_US
dc.author.commembers Dr. Fouad Hashwa
dc.author.commembers Dr. Roy Khalaf
dc.author.woa OA en_US
dc.description.physdesc 1 hard copy: xv, 53 leaves; col. ill.; 30 cm. available at RNL. en_US
dc.author.division Biology en_US
dc.author.advisor Dr. Ralph Abi-Habib
dc.keywords CRC en_US
dc.keywords Anthrax lethal toxin (PrAg/LF) en_US
dc.keywords Urokinase system en_US
dc.keywords MAPK en_US
dc.keywords Dual-targeting en_US
dc.identifier.doi https://doi.org/10.26756/th.2014.40 en_US
dc.publisher.institution Lebanese American University en_US

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