AMPK-dependent signaling modulates the suppression of invasion and migration by fenofibrate in CAL 27 oral cancer cells through NF-κB pathway

Shih Chang Tsai, Ming Hsui Tsai, Chang Fang Chiu, Chi Cheng Lu, Sheng Chu Kuo, Nai Wen Chang*, Jai Sing Yang

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

43 Scopus citations

Abstract

Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist and lipid-lowering agent, has been used worldwide for treatment of hyperlipidemia. The clinical trials demonstrate that fenofibrate possesses multiple pharmacological activities, including antitumor effects. However, the precise mechanisms in oral squamous cell carcinoma (OSCC) remain unclear. In this study, we investigated the anticancer effects of fenofibrate on the migration and invasion of human oral cancer CAL 27 cells. Fenofibrate inhibited the cell migration and invasion of CAL 27 cells by the wound healing and Boyden chamber transwell assays, respectively. In addition, fenofibrate reduced the protein expressions of MMP-1, MMP-2, MMP-7, and MMP-9 by Western blotting and inhibited enzyme activities of MMP-2/-9 using gelatin zymography assay. Results from immunoblotting analysis showed that the proteins of p-LKB1 (Ser428), LKB1, p-AMPKα (Thr172), p-AMPKα1/α2 (Ser425/Ser491), p-AMPKβ1 (Ser108), and AMPKγ1 were upregulated by fenofibrate; the levels of p-IKKα/β (Ser176) and p-IκBα were reduced in fenofibrate-treated cells. Also, fenofibrate suppressed the expressions of nuclear NF-κB p65 and p50 by immunoblotting and NF-κB DNA binding activity by EMSA assay. The anti-invasive effect of fenofibrate was attenuated by compound C [an adenosine 5′-monophosphate-activated protein kinase (AMPK) inhibitor] or dominant negative form of AMPK (DN-AMPKα1). Thus, fenofibrate considerably inhibited metastatic behaviors of CAL 27 cells might be mediated through blocking NF-κB signaling, resulting in the inhibition of MMPs; these effects were AMPK-dependent rather than PPARα signaling. Our findings provide a molecular rationale, whereby fenofibrate exerts anticancer effects and additional beneficial effects for the treatment of cancer patients.

Original languageEnglish
Pages (from-to)866-876
Number of pages11
JournalEnvironmental Toxicology
Volume31
Issue number7
DOIs
StatePublished - 01 07 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 Wiley Periodicals, Inc.

Keywords

  • AMPK
  • Fenofibrate
  • Invasion
  • Migration
  • Oral cancer CAL 27 cells

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