Abstract
Tumor necrosis factor-α (TNFα) activates both cell death and cell survival pathways, which render most cancer cells resistant to its cytotoxicity. In this study, we found that pretreatment with luteolin, a plant flavonoid, greatly sensitized TNFα-induced apoptotic cell death in a number of human cancer cell lines; including colorectal cancer COLO205, HCT116 cells and cervical cancer HeLa cells. In the search of the molecular mechanisms responsible for the sensitization effect of luteolin, we discovered that luteolin inhibited TNFα-induced activation of nuclear transcription factor-kappa B (NF-κB), the main survival factor in TNFα signaling. As a result, luteolin suppressed the expression of NF-κB-targeted antiapoptotic genes, including A20 and cellular inhibitor of apoptosis protein-1 (c-IAP1). The role of A20 and c-IAP1 was further confirmed by ectopic expression of these two genes, which significantly protected cell death induced by luteolin followed by TNFα. In addition, inhibition of NF-κB by luteolin led to augmentation and prolongation of c-Jun N-terminal kinase (JNK) activation induced by TNFα. Suppression of JNK activation, either by a synthetic JNK inhibitor (SP600125) or by overexpression of the dominant negative forms of JNK kinase 1 (JNKK1) and JNK kinase 2 (JNKK2), conferred significant protection against apoptotic cell death induced by luteolin and TNFα, suggesting that NF-κB and JNK are closely associated with the sensitization effect of luteolin. Data from this study reveal a novel function of luteolin and enhance the value of luteolin as an anticancer agent.
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Abbreviations
- TNFα:
-
tumor necrosis factor-α
- TNFR1:
-
TNF receptor 1
- NF-κB:
-
nuclear transcription factor-kappa B
- IκB:
-
inhibitor of κB
- IKK:
-
IκB kinase
- JNK:
-
c-Jun N-terminal kinase
- ActD:
-
actinomycin D
- CHX:
-
cycloheximide
- DMSO:
-
dimethyl sulfoxide
- PARP:
-
poly(ADP-ribose) polymerase
- AO:
-
acridine orange
- EB:
-
ethidium bromide
- c-IAP:
-
cellular inhibitor of apoptosis protein
- TRADD:
-
TNF receptor-associated death domain
- RIP:
-
receptor-interacting protein
- TRAF2:
-
TNF receptor-associated factor 2
- FADD:
-
Fas-associated death domain
- FLIP:
-
FLICE inhibitory protein
- G3PDH:
-
glyceraldehydes-3-phosphate dehydrogenase
- EMSA:
-
electrophoretic mobility shift assay
- CrmA:
-
cytokine response member A
- GFP:
-
green fluorescence protein
- CBP:
-
CRE-binding protein
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Acknowledgements
This study was supported in part by a research grant from the Biomedical Research Council, Singapore (BMRC 03/1/21/19/268). RX Shi is a Research Scholar supported by the National University of Singapore.
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Shi, RX., Ong, CN. & Shen, HM. Luteolin sensitizes tumor necrosis factor-α-induced apoptosis in human tumor cells. Oncogene 23, 7712–7721 (2004). https://doi.org/10.1038/sj.onc.1208046
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DOI: https://doi.org/10.1038/sj.onc.1208046
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