Embelin suppresses STAT3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase PTEN.

Even though embelin, an inhibitor of the XIAP, is known to exhibit anti-inflammatory and anti-cancer activities, very little is known about its mechanism of action. Here, we investigated whether embelin mediates its effect through interference with the signal transducer and activator of transcription 3 (STAT3) pathway. We found that embelin inhibited constitutive STAT3 activation in a variety of human cancer cell lines such as U266, DU-145, and SCC4 cells. The suppression of STAT3 was mediated through inhibition of the activation of JAK2 and c-Src. Pervanadate treatment also reversed the embelin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that embelin-induced the expression of the tyrosine phosphatase PTEN and deletion of the PTEN gene by small interfering RNA abolished the ability of embelin to inhibit STAT3 activation. Besides, embelin failed to suppress STAT3 activation in PTEN-null PC3 cells, thus indicating that the inhibitory effect of embelin on STAT3 is PTEN-dependent. Embelin down-regulated the expression of STAT3-regulated gene products; this correlated with the suppression of cell proliferation and invasion, and the induction of apoptosis through the activation of caspase-3. Overall, our results indicate that the anti-inflammatory and anti-cancer activities previously assigned to embelin may be mediated in part through the suppression of the STAT3 pathway.

Heo JY ，Kim HJ ，Kim SM ，Park KR ，Park SY ，Kim SW ，Nam D ，Jang HJ ，Lee SG ，Ahn KS ，Kim SH ，Shim BS ，Choi SH ，Ahn KS ... -  《-》

Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1.

The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an attractive target for therapy. In the present report, we investigated whether honokiol mediates its effect through interference with the STAT3 activation pathway. The effect of honokiol on STAT3 activation, associated protein kinases, and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different HCC cell lines. We found that honokiol inhibited both constitutive and inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed honokiol-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that honokiol induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Moreover, deletion of SHP-1 gene by siRNA abolished the ability of honokiol to inhibit STAT3 activation. The inhibition of STAT3 activation by honokiol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, honokiol inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, the results suggest that honokiol is a novel blocker of STAT3 activation and may have a great potential for the treatment of HCC and other cancers.

Rajendran P ，Li F ，Shanmugam MK ，Vali S ，Abbasi T ，Kapoor S ，Ahn KS ，Kumar AP ，Sethi G ... -  《-》

Janus activated kinase 2/signal transducer and activator of transcription 3 pathway mediates icariside II-induced apoptosis in U266 multiple myeloma cells.

Although the flavonoid icariside II exhibits anti-inflammatory and anti-cancer activities, its molecular targets/pathways in human multiple myeloma cells are poorly understood. To analyze the effects on signal transducer and activator of transcription 3 (STAT3) signaling and apoptosis, U266 multiple myeloma cells were treated with icariside II and performed Western blotting, electrophoretic mobility gel shift assay (EMSA), RT-PCR, proliferation assay, cell cycle analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Icariside II inhibited STAT3 activation and enhanced the expression of SHP-1 and PTEN through inhibiting Janus activated kinase 2 (JAK2) and c-Src. Icariside II down-regulated the expression of STAT3 target genes Bcl-2, Bcl-x(L), survivin, cyclin D(1), COX-2 and vascular endothelial growth factor (VEGF). Also, icariside II enhanced poly (ADP-ribose) polymerase (PARP) cleavage and caspase-3 activation. Pervanadate reversed the icariside II-mediated STAT3 inactivation and also blocked the cleavages of caspase-3 and PARP, suggesting involvement of STAT3 pathway in icariside II-induced apoptosis. Furthermore, icariside II enhanced the apoptotic effects of clinically used drugs thalidomide and bortezomib in U266 cells. Icariside II could be a potential therapeutic intervention agent alone or in combination with current drugs for multiple myeloma as a novel blocker of STAT3 signaling cascades at multiple levels, contributing to its anti-proliferative and anti-apoptosis.

Kim SH ，Ahn KS ，Jeong SJ ，Kwon TR ，Jung JH ，Yun SM ，Han I ，Lee SG ，Kim DK ，Kang M ，Chen CY ，Lee JW ，Kim SH ... -  《-》

Inhibition of JAK1/STAT3 signaling mediates compound K-induced apoptosis in human multiple myeloma U266 cells.

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in carcinogenesis. Here, the role of STAT3 pathway in the antitumor activity of an active ginseng saponin metabolite compound K (CK) was investigated in human multiple myeloma U266 cells. CK increased the cytotoxicity, accumulated the sub-G1 DNA population, cleaved poly (ADP-ribose) polymerase (PARP) and activated caspase-3 in U266 cells. Interestingly, CK inhibited phosphorylation of STAT3 and its upstream activators, the Janus activated kinase 1 (JAK1), but not JAK2. Furthermore, CK enhanced the expression of protein tyrosine phosphatase (PTP) SHP-1, but not PTEN. Additionally, CK down-regulated STAT3 target genes bcl-x(L), bcl-2, survivin, cyclin E and cyclin D1. Conversely, PTP inhibitor pervanadate reversed CK-mediated STAT3 inactivation and cleavages of caspase-3 and PARP. Overall, our findings demonstrate that JAK1/STAT3 signaling mediates CK-induced apoptosis in U266 cells and also suggest the chemopreventive potential of CK for treatment of multiple myeloma.

Park S ，Lee HJ ，Jeong SJ ，Song HS ，Kim M ，Lee HJ ，Lee EO ，Kim DH ，Ahn KS ，Kim SH ... -  《-》

Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells.

Tan SM ，Li F ，Rajendran P ，Kumar AP ，Hui KM ，Sethi G ... -  《-》