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.