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The flavonoid tangeretin activates the unfolded protein response and synergizes with imatinib in the erythroleukemia cell line K562

Sofie Lust (UGent) , Barbara Vanhoecke (UGent) , Mireille Van Gele (UGent) , Jan Philippé (UGent) , Marc Bracke (UGent) and Fritz Offner (UGent)
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Abstract
We explored the mechanism of cell death of the polymethoxyflavone tangeretin (TAN) in K562 breakpoint cluster region-abelson murine leukemia (Bcr-Abl+) cells. Flow cytometric analysis showed that TAN arrested the cells in the G(2)/M phase and stimulated an accumulation of the cells in the sub-Go phase. TAN-induced cell death was evidenced by poly(ADP)-ribose polymerase cleavage, DNA laddering fragmentation, activation of the caspase cascade and down-regulation of the antiapoptotic proteins Mcl-1 and Bcl-x(1),. Pretreatment with the pancaspase inhibitor Z-VAD-FMK_blocked caspase activation and cell cycle arrest but did not inhibit apoptosis which suggest that other cell killing mechanisms like endoplasmic reticulum (ER)-associated cell death pathways could be involved. We demonstrated that TAN-induced apoptosis was preceded by a rapid activation of the proapoptotic arm of the unfolded protein response, namely PKR-like ER kinase. This was accompanied by enhanced levels of glucose-regulated protein of 78 kDa and of spliced X-box binding protein 1. Furthermore, TAN sensitized K562 cells to the cell killing effects of imatinib via an apoptotic mechanism. In conclusion, our results suggest that TAN is able to induce apoptosis in Bcr-Abl+ cells via cell cycle arrest and the induction of the unfolded protein response, and has synergistic cytotoxicity with imatinib.
Keywords
P38 MAPK, DIFFERENTIATION, CARCINOMA CELLS, INDUCED APOPTOSIS, ENDOPLASMIC-RETICULUM STRESS, Unfolded protein response, Imatinib, Flavonoid, Apoptosis, Cell cycle arrest, DEATH, CYTOTOXICITY, INHIBITION, CASPASE-12, MECHANISM

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Chicago
LUST, SOFIE, Barbara Vanhoecke, Mireille Van Gele, Jan Philippé, Marc Bracke, and Fritz Offner. 2010. “The Flavonoid Tangeretin Activates the Unfolded Protein Response and Synergizes with Imatinib in the Erythroleukemia Cell Line K562.” Molecular Nutrition & Food Research 54 (6): 823–832.
APA
LUST, S., Vanhoecke, B., Van Gele, M., Philippé, J., Bracke, M., & Offner, F. (2010). The flavonoid tangeretin activates the unfolded protein response and synergizes with imatinib in the erythroleukemia cell line K562. MOLECULAR NUTRITION & FOOD RESEARCH, 54(6), 823–832.
Vancouver
1.
LUST S, Vanhoecke B, Van Gele M, Philippé J, Bracke M, Offner F. The flavonoid tangeretin activates the unfolded protein response and synergizes with imatinib in the erythroleukemia cell line K562. MOLECULAR NUTRITION & FOOD RESEARCH. 2010;54(6):823–32.
MLA
LUST, SOFIE, Barbara Vanhoecke, Mireille Van Gele, et al. “The Flavonoid Tangeretin Activates the Unfolded Protein Response and Synergizes with Imatinib in the Erythroleukemia Cell Line K562.” MOLECULAR NUTRITION & FOOD RESEARCH 54.6 (2010): 823–832. Print.
@article{968353,
  abstract     = {We explored the mechanism of cell death of the polymethoxyflavone tangeretin (TAN) in K562 breakpoint cluster region-abelson murine leukemia (Bcr-Abl+) cells. Flow cytometric analysis showed that TAN arrested the cells in the G(2)/M phase and stimulated an accumulation of the cells in the sub-Go phase. TAN-induced cell death was evidenced by poly(ADP)-ribose polymerase cleavage, DNA laddering fragmentation, activation of the caspase cascade and down-regulation of the antiapoptotic proteins Mcl-1 and Bcl-x(1),. Pretreatment with the pancaspase inhibitor Z-VAD-FMK\_blocked caspase activation and cell cycle arrest but did not inhibit apoptosis which suggest that other cell killing mechanisms like endoplasmic reticulum (ER)-associated cell death pathways could be involved. We demonstrated that TAN-induced apoptosis was preceded by a rapid activation of the proapoptotic arm of the unfolded protein response, namely PKR-like ER kinase. This was accompanied by enhanced levels of glucose-regulated protein of 78 kDa and of spliced X-box binding protein 1. Furthermore, TAN sensitized K562 cells to the cell killing effects of imatinib via an apoptotic mechanism. In conclusion, our results suggest that TAN is able to induce apoptosis in Bcr-Abl+ cells via cell cycle arrest and the induction of the unfolded protein response, and has synergistic cytotoxicity with imatinib.},
  author       = {Lust, Sofie and Vanhoecke, Barbara and Van Gele, Mireille and Philipp{\'e}, Jan and Bracke, Marc and Offner, Fritz},
  issn         = {1613-4125},
  journal      = {MOLECULAR NUTRITION \& FOOD RESEARCH},
  keyword      = {P38 MAPK,DIFFERENTIATION,CARCINOMA CELLS,INDUCED APOPTOSIS,ENDOPLASMIC-RETICULUM STRESS,Unfolded protein response,Imatinib,Flavonoid,Apoptosis,Cell cycle arrest,DEATH,CYTOTOXICITY,INHIBITION,CASPASE-12,MECHANISM},
  language     = {eng},
  number       = {6},
  pages        = {823--832},
  title        = {The flavonoid tangeretin activates the unfolded protein response and synergizes with imatinib in the erythroleukemia cell line K562},
  url          = {http://dx.doi.org/10.1002/mnfr.200900186},
  volume       = {54},
  year         = {2010},
}

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