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The shunting of arachidonic acid metabolism to 5-lipoxygenase and cytochrome p450 epoxygenase antagonizes the anti-cancer effect of cyclooxygenase-2 inhibition in head and neck cancer cells

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Abstract

Background

It has recently been found that 5-lipoxygenase (5-LO) and cytochrome P450-2J2 (CYP2J2), molecules capable of arachidonic acid (AA) metabolism, might promote cancer cell viability through several mechanisms similar to those of cyclooxygenase-2 (COX-2). We found that not only COX-2 expression, but also the expression of 5-LO and CYP2J2 is up-regulated in head and neck squamous cell carcinoma (HNSCC) cell lines. From these observations, we hypothesized that AA metabolism by 5-LO and/or CYP2J2 may lower the efficacy of anti-cancer effect by COX-2 inhibition.

Methods and Results

Although COX-2 was highly expressed in all cell lines tested, COX-2-specific inhibition showed little growth-inhibitory effect in some cell lines. Inhibition of COX-2 resulted in increased production of LTB4 and 14-15-DHET/EET, metabolites of 5-LO and CYP2J2, respectively. Combined knock-down of COX-2 and 5-LO or CYP2J2 by siRNA results in a decrease in cell proliferation and VEGF production. Furthermore, these results are dependent on 5-LO and CYP2J2 expression in cells.

Conclusion

Therefore, combined inhibition of COX-2 and 5-LO or CYP2J2 may be one way to overcome low efficacy of single inhibition of COX-2 in cancer cells. In addition, combined therapies should be chosen based on the expression of members of other AA metabolism pathways.

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Abbreviations

siRNA:

small interfering RNA

CYP2J2:

cytochrome P450 family 2-subfamily J-polypeptide 2

PGE2 :

prostaglandin E2

LTB4 :

Leukotriene B4

DHET:

dihydroxyeicosatrienoic acid

EET:

epoxyeicosatrienoic acid

VEGF:

vascular endothelial growth factor

5-HETE:

5-Hydroxyeicosatetraenoic acid

cytLTs:

cysteinyl-leukotrienes

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Acknowledgements

We thank Dr. William L. Smith, Dr. Thomas G. Brock and Darryl C. Zeldin for kindly providing us with the cDNA of COX-2, 5-LO and CYP2J2.

This study was supported by a grant from the national R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea [Grants no. 0620250] and BK21 project for Medicine, Dentistry and Pharmacy, Korea.

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Authors and Affiliations

  1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Seok-Woo Park, Dae-Seog Heo & Myung-Whun Sung

  2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

    Dae-Seog Heo

  3. Department of Otorhinolaryngology, Seoul National University College of Medicine, 28, Yongon-Dong, Chongno-Gu, Seoul, 110–744, Korea

    Myung-Whun Sung

  4. Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul National University Hospital, Seoul, Korea

    Myung-Whun Sung

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  1. Seok-Woo Park
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Correspondence to Myung-Whun Sung.

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Park, SW., Heo, DS. & Sung, MW. The shunting of arachidonic acid metabolism to 5-lipoxygenase and cytochrome p450 epoxygenase antagonizes the anti-cancer effect of cyclooxygenase-2 inhibition in head and neck cancer cells. Cell Oncol. 35, 1–8 (2012). https://doi.org/10.1007/s13402-011-0051-7

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