5-Hydroxy-2-Methyl-1,4-Naphthoquinone, a Vitamin K3 Analogue, Suppresses STAT3 Activation Pathway through Induction of Protein Tyrosine Phosphatase, SHP-1: Potential Role in Chemosensitization

Abstract

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.

Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH

“…These results are associated with a PLB-dependant decrease in proliferation and an increase in apoptosis in SU-treated rats. b and c) PLB treatment is associated with a significant decrease in both STAT3, nuclear factor of activated T-cells (NFAT)c2 and Sarcoma previously shown to have anti-proliferative and pro-apoptotic properties (in part, through STAT3 inhibition [20]) in cancer and vasoactive properties in bovine pulmonary arteries [54], all of which agree with a positive therapeutic effect in PAH. In this study, we have demonstrated an inhibitory effect of PLB on STAT3 activation in human PASMCs and shown that it also blocks NFAT expression and activation.…”

“…Moreover, we have demonstratede that Src activation is decreased in PLB-treated animals (figs 6b and 7c). Thus, inhibition of the Src pathway by PLB, as shown in cancer cells [20], could explain the STAT3 inhibition by PLB seen in PAH.…”

“…PLB dose-dependently decreases proliferation and promotes apoptosis. Based on the dose-response effects, we decided to use PLB at 1 mM (which also corresponds with the dose previously used in other studies [20]) and were able to significantly decrease both proliferation and resistance to apoptosis. At 1 mM, PLB in starved PAH-PASMCs (0.1% FBS) increased apoptosis measured by both TUNEL and annexin V when compared with vehicle-treated PAH-PASMCs ( fig.…”

“…Recent studies have shown that PLB downregulates the expression of survivin and growth factor receptor [16], which are implicated in PAH [9,17] and modulated by STAT3 [18,19] and NFAT [4]. More importantly, PLB was found to be an efficient STAT3 inhibitor in cancer cells [20], thus promoting apoptosis [21]. We therefore hypothesised that inhibition of the STAT3/NFAT axis by PLB would decrease PAH-PASMC proproliferative and anti-apoptotic phenotypes, thus preventing and reversing established PAH.…”

Plant-derived anticancer agents: a promising treatment for bone metastasis

“…The properties are exerted through a variety of mechanisms, including signal transducer and activator of transcription 3 (STAT3) activation, 15 induction of p53 and c-Jun N-terminal kinase expression in human nonsmall-cell lung cancer cells, 16 inhibition of the nuclear factor-kB (NF-kB)/Bcl-2 pathway 12 and by downregulating the expression of the chemokine receptor CXCR4. 17 The antitumor effects of plumbagin have been shown in several cancers including squamous cell carcinoma, 18 leukemia 19 and myeloma, 15 as well as breast, 17,20 ovarian, 21 pancreatic, 22 lung, 23 liver 24 and cervical cancers. 25 In bone, breast cancer cells increase bone resorption by producing factors such as the parathyroid hormone-related protein (PTHrP) and interleukins that stimulate the osteoblasts and increase the production of the receptor activator of NF-kB (RANK) ligand (RANKL).…”