title: Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-κB and STAT3 pathways in head and neck cancer cells.
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 factor-kappaB (NF-κB) 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-κB 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-κB 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-κB. Importantly, treatment of HNSCC cells with GS abrogated both ST- and nicotine-induced nuclear activation of NF-κB 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-κB 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.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi-110029, India.
authors.forename: Muzafar A
authors.initials: MA
authors.lastname: Macha
authors.forename: Ajay
authors.initials: A
authors.lastname: Matta
authors.forename: S S
authors.initials: SS
authors.lastname: Chauhan
authors.forename: K W Michael
authors.initials: KW
authors.lastname: Siu
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D029744:Commiphora / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005731:Ganglionic Stimulants / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014030:Tobacco, Smokeless / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D005731:Ganglionic Stimulants; D016328:NF-kappa B; D011282:Pregnenediones; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009538:Nicotine; C023617:pregna-4,17-diene-3,16-dione; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human