Tsitsipatis, Dimitrios and Jayavelu, Ashok Kumar and Mueller, Joerg P. and Bauer, Reinhard and Schmidt-Arras, Dirk and Mahboobi, Siavosh and Schnoeder, Tina M. and Heidel, Florian and Boehmer, Frank-D. (2017) Synergistic killing of FLT3ITD-positive AML cells by combined inhibition of tyrosine-kinase activity and N-glycosylation. ONCOTARGET, 8 (16). pp. 26613-26624. ISSN 1949-2553,
Full text not available from this repository. (Request a copy)Abstract
Fms-like tyrosine kinase 3 (FLT3) with internal tandem duplications (ITD) is a major oncoprotein in acute myeloid leukemia (AML), and confers an unfavorable prognosis. Interference with FLT3ITD signaling is therefore pursued as a promising therapeutic strategy. In this study we show that abrogation of FLT3ITD glycoprotein maturation using low doses of the N-glycosylation inhibitor tunicamycin has antiproliferative and pro-apoptotic effects on FLT3ITD-expressing human and murine cell lines. This effect is mediated in part by arresting FLT3ITD in an underglycosylated state and thereby attenuating FLT3ITD-driven AKT and ERK signaling. In addition, tunicamycin caused pronounced endoplasmatic reticulum stress and apoptosis through activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activation of the gene encoding CCAAT-enhancer-binding protein homologous protein (CHOP). PERK inhibition with a small molecule attenuated CHOP induction and partially rescued cells from apoptosis. Combination of tunicamycin with potent FLT3ITD kinase inhibitors caused synergistic cell killing, which was highly selective for cell lines and primary AML cells expressing FLT3ITD. Although tunicamycin is currently not a clinically applicable drug, we propose that mild inhibition of N-glycosylation may have therapeutic potential in combination with FLT3 kinase inhibitors for FLT3ITD-positive AML.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; ENDOPLASMIC-RETICULUM STRESS; INTERNAL TANDEM DUPLICATION; LINKED GLYCOSYLATION; ITD MUTATIONS; FLT3 ITD; CANCER; TUNICAMYCIN; TRANSFORMATION; INACTIVATION; acute myeloid leukemia; FLT3ITD; tunicamycin; selective cytotoxicity |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:10 |
| Last Modified: | 28 Feb 2019 06:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1031 |
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