Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1

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...

Full description

Bibliographic Details
Main Authors:	Bekdash, Amira, Darwish, Manal, Timsah, Zahra, Kassab, Elias, Ghanem, Hadi, Najjar, Vicky, Ghosn, Marwan, Nasser, Selim, El-Hajj, Hiba, Bazerbachi, Ali, Liu, Shihui, Leppla, Stephen H., Frankel, Arthur E., Abi-Habib, Ralph J.
Format:	Online
Language:	English
Published:	Neoplasia Press 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630967/

id	pubmed-4630967
recordtype	oai_dc
spelling	pubmed-46309672015-11-20 Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1 Bekdash, Amira Darwish, Manal Timsah, Zahra Kassab, Elias Ghanem, Hadi Najjar, Vicky Ghosn, Marwan Nasser, Selim El-Hajj, Hiba Bazerbachi, Ali Liu, Shihui Leppla, Stephen H. Frankel, Arthur E. Abi-Habib, Ralph J. Article 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. Neoplasia Press 2015-10-28 /pmc/articles/PMC4630967/ /pubmed/26500025 http://dx.doi.org/10.1016/j.tranon.2015.07.001 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Bekdash, Amira Darwish, Manal Timsah, Zahra Kassab, Elias Ghanem, Hadi Najjar, Vicky Ghosn, Marwan Nasser, Selim El-Hajj, Hiba Bazerbachi, Ali Liu, Shihui Leppla, Stephen H. Frankel, Arthur E. Abi-Habib, Ralph J.
spellingShingle	Bekdash, Amira Darwish, Manal Timsah, Zahra Kassab, Elias Ghanem, Hadi Najjar, Vicky Ghosn, Marwan Nasser, Selim El-Hajj, Hiba Bazerbachi, Ali Liu, Shihui Leppla, Stephen H. Frankel, Arthur E. Abi-Habib, Ralph J. Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1
author_facet	Bekdash, Amira Darwish, Manal Timsah, Zahra Kassab, Elias Ghanem, Hadi Najjar, Vicky Ghosn, Marwan Nasser, Selim El-Hajj, Hiba Bazerbachi, Ali Liu, Shihui Leppla, Stephen H. Frankel, Arthur E. Abi-Habib, Ralph J.
author_sort	Bekdash, Amira
title	Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1
title_short	Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1
title_full	Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1
title_fullStr	Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1
title_full_unstemmed	Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1
title_sort	phospho-mek1/2 and upar expression determine sensitivity of aml blasts to a urokinase-activated anthrax lethal toxin (pragu2/lf)1
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.
publisher	Neoplasia Press
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630967/
_version_	1613496603853717504

Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1

Similar Items