Abstract
We previously demonstrated that quercetin, a naturally occurring flavonoid with strong antioxidant properties, was able to enhance programmed cell death in HPB-acute lymphoblastic leukemia (ALL) cell line, derived from a human tymoma, when associated with the agonistic anti-CD95 monoclonal antibody. Here, we report that HPB-ALL cells are normally resistant to CD95-mediated apoptosis, and quercetin is able to sensitize this cell line through a mechanism independent of its antioxidant properties. In fact, other compounds structurally and functionally similar to quercetin, when associated with anti-CD95 antibody did not induce any CD95-mediated apoptosis, still maintaining their antioxidant capacity. We found that quercetin effects are mediated by the activation of PKCα. Treatment of HPB-ALL cells with quercetin slightly decreased PKCα activity, but when the flavonoid was associated with anti-CD95, the kinase activity increased by 12-fold with respect to the treatment with quercetin. In addition, overexpression of PKCα induced programmed cell death in the absence of any additional stimulus, while a kinase-defective mutant of PKCα was ineffective. Our data confirm the involvement of specific PKC isoforms in CD95 signaling and suggest, for the first time, that quercetin targets this pathway increasing apoptogenic response in a cell line resistant to CD95-mediated apoptosis.
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Abbreviations
- DCFDA:
-
2′-7′-dichlorofluorescin diacetate
- DMSO:
-
dimethylsulfoxide
- IETD-AFC:
-
Ile-Glu-Thr-Asp-7-amino-4-trifluoromethyl coumarin
- LB:
-
lysis buffer
- LEHD-AFC:
-
Leu-Glu-Hys-Asp-7-amino-4-trifluoromethyl coumarin
- PBS:
-
phosphate-buffered saline
- PCD:
-
programmed cell death
- PKC:
-
protein kinase C
- PI3K:
-
inositol 1,4,5-triphosphate kinase
- PMA:
-
12-O-tetradecanoylphorbol-13-acetate
- T-TBS:
-
Tween-20/Tris-buffered saline
- ROS:
-
reactive oxygen species
- Z-DEVD-AFC:
-
carbobenzoxy-Asp-Glu-Val-Asp-7-amino-4-trifluoromethyl coumarin
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Acknowledgements
We thank the following colleagues for providing us several reagents used in the present study: Dr Weiqun Li for PKCα expressing vector; Drs Jae-Won Soh and I Bernard Weinstein for pHACE-PKC-KR plasmid; Dr Mauro Rossi for Jurkat cell line; Dr Luigia Santella for GF109203X. We also thank Drs Giavincenzo Barba and Paola Russo for their help in statistical analysis. This work has been supported by a grant from Istituto Superiore di Sanità (Roma, Italy), research project: ‘Natural antioxidants and effects on chronic-degenerative diseases.’
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Russo, M., Palumbo, R., Mupo, A. et al. Flavonoid quercetin sensitizes a CD95-resistant cell line to apoptosis by activating protein kinase Cα. Oncogene 22, 3330–3342 (2003). https://doi.org/10.1038/sj.onc.1206493
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DOI: https://doi.org/10.1038/sj.onc.1206493
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