Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Luteolin sensitizes tumor necrosis factor-α-induced apoptosis in human tumor cells

Oncogene volume 23, pages 7712–7721 (2004)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

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

References

  • Baldwin AS . (2001). J. Clin. Invest., 107, 241–246.

  • Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, XuW, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM and Anderson DW . (2001). Proc. Natl. Acad. Sci. USA, 98, 13681–13686.

  • Birt DF, Hendrich S and Wang W . (2001). Pharmacol. Ther., 90, 157–177.

  • Chen G and Goeddel DV . (2002). Science, 296, 1634–1635.

  • Chinnaiyan AM, O'Rourke K, Tewari M and Dixit VM . (1995). Cell, 81, 505–512.

  • Darzynkiewicz Z, Bedner E, Traganos F and Murakami T . (1998). Hum. Cell, 11, 3–12.

  • Davis RJ . (2000). Cell, 103, 239–252.

  • De Smaele E, Zazzeroni F, Papa S, Nguyen DU, Jin R, Jones J, Cong R and Franzoso G . (2001). Nature, 414, 308–313.

  • Denecker G, Vercammen D, Steemans M, Vanden Berghe T, Brouckaert G, Van Loo G, Zhivotovsky B, Fiers W, Grooten J, Declercq W and Vandenabeele P . (2001). Cell Death. Differ., 8, 829–840.

  • Deng Y, Ren X, Yang L, Lin Y and Wu X . (2003). Cell, 115, 61–70.

  • Farah M, Parhar K, Moussavi M, Eivemark S and Salh B . (2003). Am. J. Physiol. Gastrointest. Liver Physiol., 285, G919–G928.

  • Gerritsen ME, Williams AJ, Neish AS, Moore S, Shi Y and Collins T . (1997). Proc. Natl. Acad. Sci. USA, 94, 2927–2932.

  • He KL and Ting AT . (2002). Mol. Cell. Biol., 22, 6034–6045.

  • Hehner SP, Hofmann TG, Droge W and Schmitz ML . (1999). J. Immunol., 163, 5617–5623.

  • Hehner SP, Hofmann TG, Ratter F, Dumont A and Droge Wand Schmitz ML . (1998). J. Biol. Chem., 273, 18117–18121.

  • Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, Kandaswami C, Middleton Jr E and Lee MT . (1999). Br. J. Pharmacol., 128, 999–1010.

  • Karin M and Ben Neriah Y . (2000). Annu. Rev. Immunol., 18, 621–663.

  • Karin M and Delhase M . (2000). Semin. Immunol., 12, 85–98.

  • Karin M and Lin A . (2002). Nat. Immunol., 3, 221–227.

  • Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ and Leder P . (1998). Immunity, 8, 297–303.

  • Kim DM, Koo SY, Jeon K, Kim MH, Lee J, Hong CY and Jeong S . (2003a). Cancer Res., 63, 621–626.

  • Kim SH, Shin KJ, Kim D, Kim YH, Han MS, Lee TG, Kim E, Ryu SH and Suh PG . (2003b). Biochem. Pharmacol., 66, 955–963.

  • Ko WG, Kang TH, Lee SJ, Kim YC and Lee BH . (2002). Phytother. Res., 16, 295–298.

  • Krikos A, Laherty CD and Dixit VM . (1992). J. Biol. Chem., 267, 17971–17976.

  • Kucharczak J, Simmons MJ, Fan Y and Gelinas C . (2003). Oncogene, 22, 8961–8982.

  • Lademann U, Kallunki T and Jaattela M . (2001). Cell Death. Differ., 8, 265–272.

  • Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP and Ma A . (2000). Science, 289, 2350–2354.

  • Li X, Yang Y and Ashwell JD . (2002). Nature, 416, 345–347.

  • Lin Y, Devin A, Rodriguez Y and Liu ZG . (1999). Genes Dev., 13, 2514–2526.

  • Liu ZG, Hsu H, Goeddel DV and Karin M . (1996). Cell, 87, 565–576.

  • Mafune K, Tanaka Y, Mimori K, Mori M, Takubo K and Makuuchi M . (1999). Clin. Cancer Res., 5, 4073–4078.

  • McGahon AJ, Martin SJ, Bissonnette RP, Mahboubi A, Shi Y, Mogil RJ, Nishioka WK and Green DR . (1995). Methods Cell Biol., 46, 153–185.

  • Micheau O, Lens S, Gaide O, Alevizopoulos K and Tschopp J . (2001). Mol. Cell. Biol., 21, 5299–5305.

  • Muzio M, Salvesen GS and Dixit VM . (1997). J. Biol. Chem., 272, 2952–2956.

  • Natoli G, Costanzo A, Ianni A, Templeton DJ, Woodgett JR, Balsano C and Levrero M . (1997). Science, 275, 200–203.

  • Petak I, Douglas L, Tillman DM, Vernes R and Houghton JA . (2000). Clin. Cancer Res., 6, 4119–4127.

  • Reinhard C, Shamoon B, Shyamala V and Williams LT . (1997). EMBO J., 16, 1080–1092.

  • Ross JA and Kasum CM . (2002). Annu. Rev. Nutr., 22, 19–34.

  • Salghetti SE, Kim SY and Tansey WP . (1999). EMBO J., 18, 717–726.

  • Shen H, Yang C, Liu J and Ong C . (2000). Free Radic. Biol. Med., 28, 1115–1124.

  • Song HY, Rothe M and Goeddel DV . (1996). Proc. Natl. Acad. Sci. USA, 93, 6721–6725.

  • Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK and Kasahara T . (2000). J. Biol. Chem., 275, 16309–16315.

  • Strasser A and Newton K . (1999). Int. J. Biochem. Cell Biol., 31, 533–537.

  • Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M and Lin A . (2001). Nature, 414, 313–317.

  • Ting AT, Pimentel-Muinos FX and Seed B . (1996). EMBO J., 15, 6189–6196.

  • Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA and Davis RJ . (2000). Science, 288, 870–874.

  • Tracey KJ and Cerami A . (1993). Annu. Rev. Cell Biol., 9, 317–343.

  • Ueda H, Yamazaki C and Yamazaki M . (2003). Biol. Pharm. Bull., 26, 560–563.

  • Wang CY, Mayo MW, Korneluk RG, Goeddel DV and Baldwin Jr AS . (1998). Science, 281, 1680–1683.

  • Wu M, Xu LG, Li X, Zhai Z and Shu HB . (2002). J. Biol. Chem., 277, 25617–25623.

  • Xagorari A, Papapetropoulos A, Mauromatis A, Economou M, Fotsis T and Roussos C . (2001). J. Pharmacol. Exp. Ther., 296, 181–187.

  • Yamamoto Y and Gaynor RB . (2001). J. Clin. Invest., 107, 135–142.

  • Yang CF, Shen HM and Ong CN . (2000). Arch. Biochem. Biophys., 380, 319–330.

  • Yang CS, Landau JM, Huang MT and Newmark HL . (2001). Annu. Rev. Nutr., 21, 381–406.

  • Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El Deiry WS, Lowe SW, Goeddel DV and Mak TW . (1998). Science, 279, 1954–1958.

Download references

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.

Author information

Authors and Affiliations

  1. Department of Community, Occupational and Family Medicine, Faculty of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117597, Republic of Singapore

    Ran-Xin Shi, Choon-Nam Ong & Han-Ming Shen

Authors
  1. Ran-Xin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Choon-Nam Ong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Han-Ming Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Han-Ming Shen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208046

Keywords

This article is cited by

Search

Advanced search

Quick links