Guggulsterone targets smokeless tobacco induced PI3K/Akt pathway in head and neck cancer cells

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Epidemiological association of head and neck cancer with smokeless tobacco (ST) emphasizes the need to unravel the molecular mechanisms implicated in cancer development, and identify pharmacologically safe agents for early intervention and prevention of disease recurrence. Guggulsterone (GS), a biosafe nutraceutical, inhibits the PI3K/Akt pathway that plays a critical role in HNSCC development. However, the potential of GS to suppress ST and nicotine (major component of ST) induced HNSCC remains unexplored. We hypothesized GS can abrogate the effects of ST and nicotine on apoptosis in HNSCC cells, in part by activation of PI3K/Akt pathway and its downstream targets, Bax and Bad. Methods and Results: Our results showed ST and nicotine treatment resulted in activation of PI3K, PDK1, Akt, and its downstream proteins - Raf, GSK3β and pS6 while GS induced a time dependent decrease in activation of PI3K/Akt pathway. ST and nicotine treatment also resulted in induction of Bad and Bax phosphorylation, increased the association of Bad with 14-3-3ζresulting in its sequestration in the cytoplasm of head and neck cancer cells, thus blocking its pro-apoptotic function. Notably, GS pre-treatment inhibited ST/nicotine induced activation of PI3K/Akt pathway, and inhibited the Akt mediated phosphorylation of Bax and Bad. Conclusions: In conclusion, GS treatment not only inhibited proliferation, but also induced apoptosis by abrogating the effects of ST/nicotine on PI3K/Akt pathway in head and neck cancer cells. These findings provide a rationale for designing future studies to evaluate the chemopreventive potential of GS in ST/nicotine associated head and neck cancer.

Original languageEnglish (US)
Article numbere14728
JournalPloS one
Volume6
Issue number2
DOIs
StatePublished - Mar 4 2011

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smokeless tobacco
Smokeless Tobacco
phosphatidylinositol 3-kinase
Head and Neck Neoplasms
Phosphatidylinositol 3-Kinases
neck
nicotine
Nicotine
Cells
Chemical activation
Phosphorylation
phosphorylation
apoptosis
Association reactions
Apoptosis
neoplasm cells
pregna-4,17-diene-3,16-dione
relapse
Dietary Supplements
functional foods

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Guggulsterone targets smokeless tobacco induced PI3K/Akt pathway in head and neck cancer cells. / Macha, Muzafar A; Matta, Ajay; Chauhan, Shyam Singh; Siu, K. W.Michael; Ralhan, Ranju.

In: PloS one, Vol. 6, No. 2, e14728, 04.03.2011.

Research output: Contribution to journalArticle

Macha, Muzafar A ; Matta, Ajay ; Chauhan, Shyam Singh ; Siu, K. W.Michael ; Ralhan, Ranju. / Guggulsterone targets smokeless tobacco induced PI3K/Akt pathway in head and neck cancer cells. In: PloS one. 2011 ; Vol. 6, No. 2.
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