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Diallyl trisulfide inhibits phorbol ester-induced tumor promotion, activation of AP-1, and expression of COX-2 in mouse skin by blocking JNK and Akt signaling.
Cancer Res. 2010 Mar 01; 70(5):1932-40.CR

Abstract

An inverse relationship exists between the consumption of garlic and the risk of certain cancers. The present study was aimed at investigating the effect of garlic constituent diallyl trisulfide (DATS) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and to explore the underlying molecular mechanisms. Pretreatment of mouse skin with different garlic-derived allyl sulfides showed DATS to be the most potent in suppressing TPA-induced COX-2 expression. DATS significantly attenuated the DNA binding of activator protein-1 (AP-1), one of the transcription factors that regulate COX-2 expression, in TPA-stimulated mouse skin. DATS also diminished TPA-induced expression of c-Jun and c-Fos, the principal components of AP-1, and blunted the activation of c-Jun NH(2)-terminal kinase (JNK) and Akt. Pharmacologic inhibition of JNK or Akt by SP600125 or LY294002, respectively, resulted in diminished AP-1 DNA binding, reduced levels of c-Jun and c-Fos, and inhibition of COX-2 expression in TPA-treated mouse skin. The JNK or Akt kinase assay, taking c-Jun fusion protein as a substrate, revealed that TPA induced JNK- or Akt-mediated c-Jun phosphorylation in mouse skin, which was significantly attenuated by DATS or respective pharmacologic inhibitors. Evaluation of antitumor-promoting effect of DATS on 7,12-dimethylbenz(a)anthracene-initiated and TPA-promoted mouse skin carcinogenesis showed that pretreatment with DATS significantly reduced the incidence and multiplicity of papillomas. Taken together, the inhibitory effects of DATS on TPA-induced AP-1 activation and COX-2 expression through modulation of JNK or Akt signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis.

Authors+Show Affiliations

National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

20179211

Citation

Shrotriya, Sangeeta, et al. "Diallyl Trisulfide Inhibits Phorbol Ester-induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin By Blocking JNK and Akt Signaling." Cancer Research, vol. 70, no. 5, 2010, pp. 1932-40.
Shrotriya S, Kundu JK, Na HK, et al. Diallyl trisulfide inhibits phorbol ester-induced tumor promotion, activation of AP-1, and expression of COX-2 in mouse skin by blocking JNK and Akt signaling. Cancer Res. 2010;70(5):1932-40.
Shrotriya, S., Kundu, J. K., Na, H. K., & Surh, Y. J. (2010). Diallyl trisulfide inhibits phorbol ester-induced tumor promotion, activation of AP-1, and expression of COX-2 in mouse skin by blocking JNK and Akt signaling. Cancer Research, 70(5), 1932-40. https://doi.org/10.1158/0008-5472.CAN-09-3501
Shrotriya S, et al. Diallyl Trisulfide Inhibits Phorbol Ester-induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin By Blocking JNK and Akt Signaling. Cancer Res. 2010 Mar 1;70(5):1932-40. PubMed PMID: 20179211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diallyl trisulfide inhibits phorbol ester-induced tumor promotion, activation of AP-1, and expression of COX-2 in mouse skin by blocking JNK and Akt signaling. AU - Shrotriya,Sangeeta, AU - Kundu,Joydeb Kumar, AU - Na,Hye-Kyung, AU - Surh,Young-Joon, Y1 - 2010/02/23/ PY - 2010/2/25/entrez PY - 2010/2/25/pubmed PY - 2010/4/9/medline SP - 1932 EP - 40 JF - Cancer research JO - Cancer Res. VL - 70 IS - 5 N2 - An inverse relationship exists between the consumption of garlic and the risk of certain cancers. The present study was aimed at investigating the effect of garlic constituent diallyl trisulfide (DATS) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and to explore the underlying molecular mechanisms. Pretreatment of mouse skin with different garlic-derived allyl sulfides showed DATS to be the most potent in suppressing TPA-induced COX-2 expression. DATS significantly attenuated the DNA binding of activator protein-1 (AP-1), one of the transcription factors that regulate COX-2 expression, in TPA-stimulated mouse skin. DATS also diminished TPA-induced expression of c-Jun and c-Fos, the principal components of AP-1, and blunted the activation of c-Jun NH(2)-terminal kinase (JNK) and Akt. Pharmacologic inhibition of JNK or Akt by SP600125 or LY294002, respectively, resulted in diminished AP-1 DNA binding, reduced levels of c-Jun and c-Fos, and inhibition of COX-2 expression in TPA-treated mouse skin. The JNK or Akt kinase assay, taking c-Jun fusion protein as a substrate, revealed that TPA induced JNK- or Akt-mediated c-Jun phosphorylation in mouse skin, which was significantly attenuated by DATS or respective pharmacologic inhibitors. Evaluation of antitumor-promoting effect of DATS on 7,12-dimethylbenz(a)anthracene-initiated and TPA-promoted mouse skin carcinogenesis showed that pretreatment with DATS significantly reduced the incidence and multiplicity of papillomas. Taken together, the inhibitory effects of DATS on TPA-induced AP-1 activation and COX-2 expression through modulation of JNK or Akt signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/20179211/Diallyl_trisulfide_inhibits_phorbol_ester_induced_tumor_promotion_activation_of_AP_1_and_expression_of_COX_2_in_mouse_skin_by_blocking_JNK_and_Akt_signaling_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=20179211 DB - PRIME DP - Unbound Medicine ER -