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(E)-2,4-Bis(p-hydroxyphenyl)-2-butenal inhibits tumor growth via suppression of NF-κB and induction of death receptor 6

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Abstract

The Maillard reaction products are known to be effective in chemoprevention. Here, we focused on the anti-cancer effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal on in vitro and in vivo colon cancer. We analysed the anti-cancer activity of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal on colon cancer cells by using cell cycle and apoptosis analysis. To elucidate it’s mechanism, NF-κB DNA binding activity, docking model as well as pull-down assay. Further, a xenograft model of colon cancer was studied to test the in vivo effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal. (E)-2,4-Bis(p-hydroxyphenyl)-2-butenal inhibited colon cancer cells (SW620 and HCT116) growth followed by induction of apoptosis in a concentration-dependent manner via down-regulation of NF-κB activity. In docking model as well as pull-down assay, (E)-2,4-bis(p-hydroxyphenyl)-2-butenal directly binds to three amino acid residues of IKKβ, thereby inhibited IKKβ activity in addition to induction of death receptor 6 (DR6) as well as their target apoptotic genes. Finally, (E)-2,4-bis(p-hydroxyphenyl)-2-butenal suppressed anchorage-independent cancer cell growth, and tumor growth in xenograft model accompanied with apoptosis through inhibition of IKKβ/NF-κB activity, and overexpression of DR6. These results suggest that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal inhibits colon cancer cell growth through inhibition of IKKβ/NF-κB activity and induction of DR6 expression.

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Abbreviations

NF-κB:

Nuclear transcription factor-κB

STAT:

Signal transducers and activators of transcription

DR:

Dearth receptor

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) Grant by the Korea government (MEST; MRC, 2012-0029480), and by the Ministry of Trade, Industry and Energy (MOTIE, 1415126993) through the fostering project of Osong Academy-Industry Convergence (BAIO).

Conflict of interest

None declared.

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Authors and Affiliations

  1. College of Pharmacy and Medical Research Center, Chungbuk National University, 12, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763, South Korea

    Jung Ok Ban, Young-Suk Jung, Dae Hwan Kim, Kyung-Ran Park, Hyung-Mun Yun, Nam Jin Lee, Hee Pom Lee, Sang-Bae Han & Jin Tae Hong

  2. Department of Biochemistry, College of Medicine, Soonchunhyang University, Choenan, 330-090, South Korea

    Jeong-Hyun Shim

  3. Agriculture, Life and Environments Sciences, Chungbuk National University, 12 Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763, South Korea

    Heon-Sang Jeong

  4. Department of Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Yun-Hee Lee

  5. Department of Chemistry and Biochemistry, Brigham Young University, C409 BNSN, Provo, UT, 84602, USA

    Young Wan Ham

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  1. Jung Ok Ban
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Corresponding author

Correspondence to Jin Tae Hong.

Additional information

J. O. Ban and Y.-S. Jung contributed equally to this work.

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Supplementary Fig. 1

Effect of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal on the expression of DRs and cancer cell growth in lung cancer cells. a The cells were treated with different concentrations (10–40 μg/ml) of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal at 37 °C for 12 h. Expression of death receptor 5 and 6 was detected by western blotting using specific antibodies. β-Actin protein was used as an internal control. Each blot is representative of three independent experimental results. b Cells were transfected with 100 nM DR5 and DR6 siRNA and treated with 30 μg/ml of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal, or cells were treated with 30 μg/ml of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal for 24 h. Cell viability was determined by direct cell counting using trypan blue as described in “Materials and methods” section. Values are the mean ± SD of three experiments, each performed in triplicate (PPTX 371 kb)

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Ban, J.O., Jung, YS., Kim, D.H. et al. (E)-2,4-Bis(p-hydroxyphenyl)-2-butenal inhibits tumor growth via suppression of NF-κB and induction of death receptor 6. Apoptosis 19, 165–178 (2014). https://doi.org/10.1007/s10495-013-0903-x

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