Identification of brefelamide as a novel inhibitor of osteopontin that suppresses invasion of A549 lung cancer cells

Jing Zhang, Osamu Yamada, Shinya Kida, Yoshihisa Matsushita, Shinya Murase, Toshio Hattori, Yuzuru Kubohara, Haruhisa Kikuchi, Yoshiteru Oshima

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

The contribution of aberrant osteopontin (OPN) expression to tumor progression and metastasis has been documented in a wide spectrum of malignancies, and targeted inhibition of OPN has therefore emerged as an attractive strategy for cancer therapy. Transcription of OPN is regulated by various transcription factors, and our recently published study demonstrated that downregulation of OPN is an important event in the TGF-β cytostatic program. We report here that brefelamide exerts an inhibitory effect on OPN expression and function in A549 human lung carcinoma cells. The promoter, RNA, and protein levels of OPN were decreased in brefelamide-treated A549 cells, which was accompanied by reduced invasive ability in vitro. OPN inhibition by brefelamide was largely abrogated by disruption of a putative TGF-β inhibitory element in the OPN promoter. Treatment with brefelamide induced Smad4 expression, and knockdown of Smad4 by RNA interference partially diminished the inhibitory effect of brefelamide on OPN. These results indicate that brefelamide inhibited OPN-mediated cell invasion through restoration of the OPN repression by TGF-β/Smad signaling. Together with the reported antiproliferative property, our findings suggest that brefelamide might serve as a potential candidate for the development of a new antitumor and antimetastatic agent.

Original languageEnglish
Pages (from-to)2357-2364
Number of pages8
JournalOncology reports
Volume36
Issue number4
DOIs
Publication statusPublished - 2016 Oct

Keywords

  • Brefelamide
  • Lung cancer
  • Osteopontin
  • Smad4
  • TGF-β

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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