The activation of signal transducers and activators of transcription 3 (STAT3) has been linked with
carcinogenesis through survival, proliferation, and angiogenesis of
tumor cells. Agents that can suppress STAT3 activation have potential not only for prevention but also for treatment of
cancer. In the present report, we investigated whether
5-hydroxy-2-methyl-1,4-naphthoquinone (
plumbagin), an analogue of
vitamin K, and isolated from chitrak (Plumbago zeylanica), an Ayurvedic medicinal plant, can modulate the STAT3 pathway. We found that
plumbagin inhibited both constitutive and
interleukin 6-inducible STAT3 phosphorylation in
multiple myeloma (MM) cells and this correlated with the inhibition of c-Src, Janus-activated
kinase (JAK)1, and JAK2 activation.
Vanadate, however, reversed the
plumbagin-induced downregulation of STAT3 activation, suggesting the involvement of a
protein tyrosine phosphatase. Indeed, we found that
plumbagin induced the expression of the
protein tyrosine phosphatase, SHP-1, and silencing of the SHP-1 abolished the effect of
plumbagin. This agent also downregulated the expression of STAT3-regulated
cyclin D1, Bcl-xL, and
vascular endothelial growth factor; activated
caspase-3; induced
poly (ADP ribose) polymerase cleavage; and increased the sub-G(1) population of MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the
plumbagin-induced apoptosis. When compared with
AG490, a rationally designed STAT3/JAK2 inhibitor,
plumbagin was found more potent in suppressing the proliferation of cells.
Plumbagin also significantly potentiated the apoptotic effects of
thalidomide and
bortezomib in MM cells. Overall, these results suggest that the
plumbagin inhibits STAT3 activation pathway through the induction of SHP-1 and this may mediate the sensitization of STAT3 overexpressing
cancers to chemotherapeutic agents.