Gambogic Acid Inhibits STAT3 Phosphorylation through Activation of Protein Tyrosine Phosphatase SHP-1: Potential Role in Proliferation and Apoptosis

Abstract

The transcription factor, signal transducer and activator of transcription 3 (STAT3), is associated with proliferation, survival, and metastasis of cancer cells. We investigated whether gambogic acid (GA), a xanthone derived from the resin of traditional Chinese medicine, Gamboge hanburyi (mangosteen), can regulate the STAT3 pathway, leading to suppression of growth and sensitization of cancer cells. We found that GA induced apoptosis in human multiple myeloma cells that correlated with the inhibition of both constitutive and inducible STAT3 activation. STAT3 phosphorylation at both tyrosine residue 705 and serine residue 727 was inhibited by GA. STAT3 suppression was mediated through the inhibition of activation of the protein tyrosine kinases Janus-activated kinase (JAK) 1, and JAK2. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the GA-induced down-regulation of STAT3, suggesting the involvement of a PTP. We also found that GA induced the expression of the PTP SHP-1. Deletion of the SHP-1 gene by small interfering RNA suppressed the ability of GA to inhibit STAT3 activation and to induce apoptosis, suggesting the critical role of SHP-1 in its action. Moreover, GA down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) proteins, and this correlated with suppression of proliferation and induction of apoptosis. Overall, these results suggest that GA blocks STAT3 activation, leading to suppression of tumor cell proliferation and induction of apoptosis.

Effects of gambogic acid on the activation of caspase-3 and downregulation of SIRT1 in RPMI-8226 multiple myeloma cells via the accumulation of ROS

“…GA, the major active ingredient of gamboges secreted from the Garcinia hanburryi tree, has antitumor properties in solid tumors of various derivations in vitro and in vivo (27). The mechanisms of the anticancer activities of GA are complex and the most significant contributor has yet to be identified.…”

Recent Research on Bioactive Xanthones from Natural Medicine: Garcinia hanburyi

“…Gambogic acid showed both growth arrest and apoptosis induction effects on Jurkat cells by significantly suppressing the expression of nucleophosmin, which indicated the fact that nucleophosmin and some nucleoporins might serve as new targets of gambogic acid (69). Gambogic acid inhibited tumor cell proliferation by blocking STAT3 activation which associated with proliferation, metastasis, and survival of cancer cells (70). The result of the in vitro research on K562 cells suggests that gambogic acid showed its anti-leukemia effects partially by suppressing the expression level of hERG channel in K562 cells, indicating that gambogic acid can be a promising antitumor agent against leukemia with a mechanism of inhibiting the hERG channel (71).…”

Potential Therapeutic Effects of Natural Extracts in Multiple Myeloma

“…Prasad et al [3] found that GA induced MM cell apoptosis that correlated with inhibition of both constitutive and IL-6-induced STAT3 activation in a dose-and time-dependent manner. STAT3 suppression is mediated through the inhibition of activation of JAK1 and JAK2.…”

“…Over the last decade, studies show that GA [3] , Curcumin [32] , Resveratrol [33] and Icaritin [28] have shown significant efficacy in blocking STAT3 activation and thereby inducing apoptosis in multiple myeloma cells. Prasad et al [3] found that GA induced MM cell apoptosis that correlated with inhibition of both constitutive and IL-6-induced STAT3 activation in a dose-and time-dependent manner.…”

“…Because of their capacity to bind multiple targets, natural products may have an advantage over rationally designed mono-targeted agents in the treatment of multiple myeloma with multi-aspect abnormalities [3] . Most importantly, they show no or minor toxicity towards normal epithelial and normal peripheral blood and myeloid cells, indicating a therapeutic window.…”