Resveratrol (trans-3,5,4′-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-κB
Article first published online: 26 APR 2011
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Molecular Nutrition & Food Research
Special Issue: Resveratrol – Current Status and Outlook
Volume 55, Issue 8, pages 1207–1218, August 2011
How to Cite
Singh, N. P., Singh, U. P., Hegde, V. L., Guan, H., Hofseth, L., Nagarkatti, M. and Nagarkatti, P. S. (2011), Resveratrol (trans-3,5,4′-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-κB. Mol. Nutr. Food Res., 55: 1207–1218. doi: 10.1002/mnfr.201000576
- Issue published online: 3 AUG 2011
- Article first published online: 26 APR 2011
- Manuscript Accepted: 17 FEB 2011
- Manuscript Revised: 10 FEB 2011
- Manuscript Received: 18 NOV 2010
- National Institutes of Health Grants. Grant Numbers: P01-AT03961, R01-ES09098, R01-DA016545
Scope: Understanding the molecular mechanisms through which natural products and dietary supplements exhibit anticancer properties is crucial and can lead to drug discovery and chemoprevention. The current study sheds new light on the mode of action of resveratrol (RES), a plant-derived polyphenolic compound, against EL-4 lymphoma growth.
Methods and results: Immuno-compromised NOD/SCID mice injected with EL-4 tumor cells and treated with RES (100 mg/kg body weight) showed delayed development and progression of tumor growth and increased mean survival time. RES caused apoptosis in EL4 cells through activation of aryl hydrocarbon receptor (AhR) and upregulation of Fas and FasL expression in vitro. Blocking of RES-induced apoptosis in EL4 cells by FasL mAb, cleavage of caspases and PARP, and release of cytochorme c, demonstrated the participation of both extrinsic and intrinsic pathways of apoptosis. RES also induced upregulation of silent mating type information regulation 2 homolog, 1 (SIRT1) and downregulation of nuclear factor kappa B (NF-κB) in EL4 cells. siRNA-mediated downregulation of SIRT1 in EL4 cells increased the activation of NF-κB but decreased RES-mediated apoptosis, indicating the critical role of SIRT1 in apoptosis via blocking activation of NF-κB.
Conclusion: These data suggest that RES-induced SIRT1 upregulation promotes tumor cell apoptosis through negative regulation of NF-κB, leading to suppression of tumor growth.