Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)
In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-10-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523315000571 |
| _version_ | 1828472321142161408 |
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| author | Amira Bekdash Manal Darwish Zahra Timsah Elias Kassab Hadi Ghanem Vicky Najjar Marwan Ghosn Selim Nasser Hiba El-Hajj Ali Bazerbachi Shihui Liu Stephen H. Leppla Arthur E. Frankel Ralph J. Abi-Habib |
| author_facet | Amira Bekdash Manal Darwish Zahra Timsah Elias Kassab Hadi Ghanem Vicky Najjar Marwan Ghosn Selim Nasser Hiba El-Hajj Ali Bazerbachi Shihui Liu Stephen H. Leppla Arthur E. Frankel Ralph J. Abi-Habib |
| author_sort | Amira Bekdash |
| collection | DOAJ |
| description | In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34+ bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML. |
| first_indexed | 2024-12-11T05:28:16Z |
| format | Article |
| id | doaj.art-e3a546f6ff5d4a54b4c56054715b8842 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-11T05:28:16Z |
| publishDate | 2015-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-e3a546f6ff5d4a54b4c56054715b88422022-12-22T01:19:31ZengElsevierTranslational Oncology1936-52332015-10-0185347357Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)Amira Bekdash0Manal Darwish1Zahra Timsah2Elias Kassab3Hadi Ghanem4Vicky Najjar5Marwan Ghosn6Selim Nasser7Hiba El-Hajj8Ali Bazerbachi9Shihui Liu10Stephen H. Leppla11Arthur E. Frankel12Ralph J. Abi-Habib13Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut 1102 2801, LebanonDepartment of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut 1102 2801, LebanonSchool of Molecular & Cellular Biology, University of Leeds, Leeds, LS2 9JT, UKDepartment of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut 1102 2801, LebanonDepartment of Internal Medicine, School of Medicine, Lebanese American University, Beirut 1102-2801, LebanonDepartment of Pathology, School of Medicine, Lebanese American University, Beirut 1102-2801, LebanonDepartment of Pathology, School of Medicine, Lebanese American University, Beirut 1102-2801, LebanonDepartment of Pathology, School of Medicine, Lebanese American University, Beirut 1102-2801, LebanonDepartment of Internal Medicine and Experimental Pathology, School of Medicine, American University of Beirut, Lebanon; Department of Immunology and Microbiology, School of Medicine, American University of Beirut, LebanonDepartment of Internal Medicine, School of Medicine, American University of Beirut, Lebanon; Department of Anatomy, School of Medicine, American University of Beirut, Lebanon; Department of Cell Biology and Physiological Sciences, School of Medicine, American University of Beirut, LebanonMicrobial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas 75390Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut 1102 2801, Lebanon; Address all correspondence to: Ralph J. Abi-Habib, Lebanese American University School of Arts and Sciences, Beirut 1102 2801, Lebanon.In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34+ bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML.http://www.sciencedirect.com/science/article/pii/S1936523315000571 |
| spellingShingle | Amira Bekdash Manal Darwish Zahra Timsah Elias Kassab Hadi Ghanem Vicky Najjar Marwan Ghosn Selim Nasser Hiba El-Hajj Ali Bazerbachi Shihui Liu Stephen H. Leppla Arthur E. Frankel Ralph J. Abi-Habib Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF) Translational Oncology |
| title | Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF) |
| title_full | Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF) |
| title_fullStr | Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF) |
| title_full_unstemmed | Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF) |
| title_short | Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF) |
| title_sort | phospho mek1 2 and upar expression determine sensitivity of aml blasts to a urokinase activated anthrax lethal toxin pragu2 lf |
| url | http://www.sciencedirect.com/science/article/pii/S1936523315000571 |
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