Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-κB and STAT3 pathways in head and neck cancer cells

Muzafar A. Macha, Ajay Matta, S. S. Chauhan, K. W. Michael Siu, Ranju Ralhan

Research output: Contribution to journalArticle

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Abstract

Understanding the molecular pathways perturbed in smokeless tobacco- (ST) associated head and neck squamous cell carcinoma (HNSCC) is critical for identifying novel complementary agents for effective disease management. Activation of nuclear factorkappaB (NF-kB) and cyclooxygenase-2 (COX-2) was reported in ST-associated HNSCC by us [Sawhney,M. et al. (2007) Expression of NF-kappaB parallels COX-2 expression in oral precancer and cancer: association with smokeless tobacco. Int. J. Cancer, 120, 2545-2556]. In search of novel agents for treatment of HNSCC, we investigated the potential of guggulsterone (GS), (4,17(20)-pregnadiene-3,16-dione), a biosafe nutraceutical, in inhibiting ST- and nicotine-induced activation of NF-kB and signal transducer and activator of transcription (STAT) 3 pathways in HNSCC cells. GS inhibited the activation of NF-κB and STAT3 proteins in head and neck cancer cells. This inhibition of NF-kB by GS resulted from decreased phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha the inhibitory subunit of NF-kB. Importantly, treatment of HNSCC cells with GS abrogated both ST- and nicotine-induced nuclear activation of NF-kB and pSTAT3 proteins and their downstream targets COX-2 and vascular endothelial growth factor. Furthermore, GS treatment decreased the levels of ST- and nicotine-induced secreted interleukin-6 in culture media of HNSCC cells. In conclusion, our findings demonstrated that GS treatment abrogates the effects of ST and nicotine on activation of NF-kB and STAT3 pathways in HNSCC cells that contribute to inflammatory and angiogenic responses as well as its progression and metastasis. These findings provide a biologic rationale for further clinical investigation of GS as an effective complementary agent for inhibiting ST-induced head and neck cancer.

Original languageEnglish (US)
Pages (from-to)368-380
Number of pages13
JournalCarcinogenesis
Volume32
Issue number3
DOIs
StatePublished - Mar 10 2011

Fingerprint

Smokeless Tobacco
Head and Neck Neoplasms
Nicotine
Cyclooxygenase 2
STAT3 Transcription Factor
Pregnadienes
pregna-4,17-diene-3,16-dione
NF-kappa B
Mouth Neoplasms
Disease Management
Dietary Supplements
Carcinoma, squamous cell of head and neck
Vascular Endothelial Growth Factor A
Culture Media
Interleukin-6
B-Lymphocytes
Phosphorylation
Neoplasm Metastasis
Light
Peptides

ASJC Scopus subject areas

  • Cancer Research

Cite this

Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-κB and STAT3 pathways in head and neck cancer cells. / Macha, Muzafar A.; Matta, Ajay; Chauhan, S. S.; Michael Siu, K. W.; Ralhan, Ranju.

In: Carcinogenesis, Vol. 32, No. 3, 10.03.2011, p. 368-380.

Research output: Contribution to journalArticle

Macha, Muzafar A. ; Matta, Ajay ; Chauhan, S. S. ; Michael Siu, K. W. ; Ralhan, Ranju. / Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-κB and STAT3 pathways in head and neck cancer cells. In: Carcinogenesis. 2011 ; Vol. 32, No. 3. pp. 368-380.
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