Ginkgetin, a biflavone from Ginkgo biloba leaves, is known to exhibit antiinflammatory, antifungal, neuroprotective, and antitumor activities, but its precise mechanism of action has not been fully elucidated. Because the aberrant activation of STAT3 has been linked with regulation of
inflammation, proliferation, invasion, and
metastasis of
tumors, we hypothesized that
ginkgetin modulates the activation of STAT3 in
tumor cells. We found that
ginkgetin clearly suppressed constitutive phosphorylation of STAT3 through inhibition of the activation of upstream JAK1 and c-
Src kinases and nuclear translocation of STAT3 on both A549 and FaDu cells. Treatment with
sodium pervanadate reversed the
ginkgetin-induced down-modulation of STAT3, thereby indicating a critical role for a PTP. We also found that
ginkgetin strongly induced the expression of the SHP-1 and PTEN
proteins and its mRNAs. Further, deletion of SHP-1 and PTEN genes by
siRNA suppressed the induction of SHP-1 and PTEN, and reversed the inhibition of STAT3 activation.
Ginkgetin induced apoptosis as characterized by an increased accumulation of cells in subG1 phase, positive
Annexin V binding, loss of mitochondrial membrane potential, down-regulation of STAT3-regulated gene products, and cleavage of PARP. Overall,
ginkgetin abrogates STAT3 signaling pathway through induction of SHP-1 and PTEN
proteins, thus attenuating STAT3 phosphorylation and
tumorigenesis.