about a year and a half ago, someone posted a question--were there natural inhibitors of PI3K. Several posted articles, but I just found this one which seems all the more timely as we have been discussing the different isoforms of CLA recently:
cis-9,trans-11-Conjugated linoleic acid down-regulates phorbol ester-induced NF-B activation and subsequent COX-2 expression in hairless mouse skin by targeting IB kinase and PI3K-Akt
Dal-Mi Hwang1, Joydeb Kumar Kundu1, Jun-Wan Shin1, Jung-Chul Lee1, Hyong Joo Lee2 and Young-Joon Surh1,*
1 National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy Seoul 151-742, South Korea
2 Department of Food Science and Technology, College of Agriculture and Life Sciences, Seoul National University Seoul 151-742, South Korea
*To whom correspondence should be addressed at: College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-ku, Seoul 151-742, Korea. Tel: +82 2 880 7845; Fax: +82 2 874 9775; Email:
surh@plaza.snu.ac.kr
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-B 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-B by blocking phosphorylation and subsequent degradation of IB. 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-B by 9Z,11E-CLA, we investigated its effect on TPA-induced activation of IB kinase (IKK), an upstream kinase that regulates NF-B via phosphorylation and degradation of IB. 9Z,11E-CLA treatment down-regulated phosphorylation and catalytic activities of IKK/ß in TPA-treated mouse skin. Co-treatment of mouse skin with the IKKß-specific inhibitor SC-514 (1 µmol) attenuated TPA-induced activation of Akt and NF-B, and also the expression of COX-2 in hairless mouse skin. Taken together, 9Z,11E-CLA inhibits NF-B 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.
Abbreviations: CLA, Conjugated linoleic acid; COX-2, cyclooxygenase-2; TPA, 12-O-tetradecanoylphorbol-13-acetate; NF-B, nuclear factor-kappaB; ERK, extracellular signal-regulated protein kinase; IKK, IB kinase