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cis-9,trans-11-conjugated linoleic acid down-regulates phorbol ester-induced NF-kappaB activation and subsequent COX-2 expression in hairless mouse skin by targeting IkappaB kinase and PI3K-Akt.
Carcinogenesis. 2007 Feb; 28(2):363-71.C

Abstract

Conjugated linoleic acid (CLA) has been reported to inhibit mouse skin carcinogenesis, particularly in the promotion stage, but underlying molecular mechanisms remain poorly understood. Since persistent induction of cyclooxygenase-2 (COX-2) is frequently implicated in carcinogenesis, we investigated the effect of cis-9,trans-11-CLA (9Z,11E-CLA) on the tumor promoter-induced COX-2 expression in HR-1 hairless mouse skin in vivo. Topical application of 9Z,11E-CLA caused significant inhibition of COX-2 expression at 6 h induced by 10 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) in HR-1 mouse skin. Since NF-kappaB is known to regulate COX-2 gene expression, we determined the effect of 9Z,11E-CLA on TPA-induced activation of this transcription factor. Treatment of mouse skin with 9Z,11E-CLA reduced TPA-induced DNA binding as well as nuclear translocation of NF-kappaB by blocking phosphorylation and subsequent degradation of IkappaBalpha. In addition, 9Z,11E-CLA attenuated TPA-induced phosphorylation of extracellular signal-regulated protein kinase, p38 mitogen-activated protein kinase and Akt. To further elucidate the molecular mechanism underlying the inactivation of NF-kappaB by 9Z,11E-CLA, we investigated its effect on TPA-induced activation of IkappaB kinase (IKK), an upstream kinase that regulates NF-kappaB via phosphorylation and degradation of IkappaBalpha. 9Z,11E-CLA treatment down-regulated phosphorylation and catalytic activities of IKKalpha/beta in TPA-treated mouse skin. Co-treatment of mouse skin with the IKKbeta-specific inhibitor SC-514 (1 micromol) attenuated TPA-induced activation of Akt and NF-kappaB, and also the expression of COX-2 in hairless mouse skin. Taken together, 9Z,11E-CLA inhibits NF-kappaB driven-COX-2 expression by blocking the IKK and PI3K-Akt signaling in TPA-treated hairless mouse skin in vivo, which may account for its previously reported anti-tumor promoting effects.

Authors+Show Affiliations

Hwang DM
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul 151-742, South Korea.
Kundu JK
No affiliation info available
Shin JW
No affiliation info available
Lee JC
No affiliation info available
Lee HJ
No affiliation info available
Surh YJ
No affiliation info available

MeSH

AnimalsBase SequenceCyclooxygenase 2DNA PrimersEnzyme ActivationI-kappa B KinaseLinoleic Acids, ConjugatedMaleMiceMice, HairlessNF-kappa BPhosphatidylinositol 3-KinasesPhosphorylationProto-Oncogene Proteins c-aktSkinTetradecanoylphorbol Acetate

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16950795

Citation

Hwang, Dal-Mi, et al. "Cis-9,trans-11-conjugated Linoleic Acid Down-regulates Phorbol Ester-induced NF-kappaB Activation and Subsequent COX-2 Expression in Hairless Mouse Skin By Targeting IkappaB Kinase and PI3K-Akt." Carcinogenesis, vol. 28, no. 2, 2007, pp. 363-71.
Hwang DM, Kundu JK, Shin JW, et al. Cis-9,trans-11-conjugated linoleic acid down-regulates phorbol ester-induced NF-kappaB activation and subsequent COX-2 expression in hairless mouse skin by targeting IkappaB kinase and PI3K-Akt. Carcinogenesis. 2007;28(2):363-71.
Hwang, D. M., Kundu, J. K., Shin, J. W., Lee, J. C., Lee, H. J., & Surh, Y. J. (2007). Cis-9,trans-11-conjugated linoleic acid down-regulates phorbol ester-induced NF-kappaB activation and subsequent COX-2 expression in hairless mouse skin by targeting IkappaB kinase and PI3K-Akt. Carcinogenesis, 28(2), 363-71.
Hwang DM, et al. Cis-9,trans-11-conjugated Linoleic Acid Down-regulates Phorbol Ester-induced NF-kappaB Activation and Subsequent COX-2 Expression in Hairless Mouse Skin By Targeting IkappaB Kinase and PI3K-Akt. Carcinogenesis. 2007;28(2):363-71. PubMed PMID: 16950795.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - cis-9,trans-11-conjugated linoleic acid down-regulates phorbol ester-induced NF-kappaB activation and subsequent COX-2 expression in hairless mouse skin by targeting IkappaB kinase and PI3K-Akt. AU - Hwang,Dal-Mi, AU - Kundu,Joydeb Kumar, AU - Shin,Jun-Wan, AU - Lee,Jung-Chul, AU - Lee,Hyong Joo, AU - Surh,Young-Joon, Y1 - 2006/08/31/ PY - 2006/9/5/pubmed PY - 2007/3/27/medline PY - 2006/9/5/entrez SP - 363 EP - 71 JF - Carcinogenesis JO - Carcinogenesis VL - 28 IS - 2 N2 - Conjugated linoleic acid (CLA) has been reported to inhibit mouse skin carcinogenesis, particularly in the promotion stage, but underlying molecular mechanisms remain poorly understood. Since persistent induction of cyclooxygenase-2 (COX-2) is frequently implicated in carcinogenesis, we investigated the effect of cis-9,trans-11-CLA (9Z,11E-CLA) on the tumor promoter-induced COX-2 expression in HR-1 hairless mouse skin in vivo. Topical application of 9Z,11E-CLA caused significant inhibition of COX-2 expression at 6 h induced by 10 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) in HR-1 mouse skin. Since NF-kappaB is known to regulate COX-2 gene expression, we determined the effect of 9Z,11E-CLA on TPA-induced activation of this transcription factor. Treatment of mouse skin with 9Z,11E-CLA reduced TPA-induced DNA binding as well as nuclear translocation of NF-kappaB by blocking phosphorylation and subsequent degradation of IkappaBalpha. In addition, 9Z,11E-CLA attenuated TPA-induced phosphorylation of extracellular signal-regulated protein kinase, p38 mitogen-activated protein kinase and Akt. To further elucidate the molecular mechanism underlying the inactivation of NF-kappaB by 9Z,11E-CLA, we investigated its effect on TPA-induced activation of IkappaB kinase (IKK), an upstream kinase that regulates NF-kappaB via phosphorylation and degradation of IkappaBalpha. 9Z,11E-CLA treatment down-regulated phosphorylation and catalytic activities of IKKalpha/beta in TPA-treated mouse skin. Co-treatment of mouse skin with the IKKbeta-specific inhibitor SC-514 (1 micromol) attenuated TPA-induced activation of Akt and NF-kappaB, and also the expression of COX-2 in hairless mouse skin. Taken together, 9Z,11E-CLA inhibits NF-kappaB driven-COX-2 expression by blocking the IKK and PI3K-Akt signaling in TPA-treated hairless mouse skin in vivo, which may account for its previously reported anti-tumor promoting effects. SN - 0143-3334 UR - https://www.unboundmedicine.com/medline/citation/16950795/cis_9trans_11_conjugated_linoleic_acid_down_regulates_phorbol_ester_induced_NF_kappaB_activation_and_subsequent_COX_2_expression_in_hairless_mouse_skin_by_targeting_IkappaB_kinase_and_PI3K_Akt_ DB - PRIME DP - Unbound Medicine ER -