Zerumbone inhibits growth of hormone refractory prostate cancer cells by inhibiting JAK2/STAT3 pathway and increases paclitaxel sensitivity

Abstract

Zerumbone, a phytochemical isolated from Zingiber zerumbet has been shown previously to exhibit antineoplastic activity. But, the effect of zerumbone in prostate cancer has not been evaluated. Prostate cancer is frequently associated with elevated levels of interleukin-6 (IL-6), which exerts its oncogenic effects through activation of Janus kinase 2 (JAK2) followed by activation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Here, we investigated whether the anticancer effects of zerumbone are mediated through inhibition of the JAK2/STAT3 signaling pathway and whether zerumbone can increase the paclitaxel (PTX) sensitivity of prostate cancer cells. Zerumbone exerted significant cytotoxicity of DU145 versus PC3 prostate cancer cells through cell cycle arrest at G0/G1 phase followed by apoptosis. Zerumbone selectively inhibited JAK2 in both DU145 and PC3 cells. However, the biological axis of IL-6/JAK2/STAT3 was inhibited only in DU145 cells as no STAT3 phosphorylation was detected in PC3 cells even after IL-6 stimulation. Other signaling pathways in DU145 cells remained unaffected. The expression of prostate cancer-associated genes, including cyclin D1, IL-6, COX2, and ETV1, was blocked. Zerumbone also synergistically increased the sensitivity to PTX. Further preclinical study might reveal the potential use of zerumbone as a chemotherapeutic agent for hormone refractory prostate cancer where IL-6/JAK2/STAT3 signaling is aberrantly active and may be combined with PTX.

Inhibition of JAK2 Reverses Paclitaxel Resistance in Human Ovarian Cancer Cells

“…Moreover, JAK2 is required for interleukin-6Yinduced proliferation and survival in DU145 prostate cancer cells, and inhibition of JAK2 using zerumbone causes cell cycle arrest and increases sensitivity to paclitaxel. 12 Loss of JAK2 is embryonically lethal because of failure of hematopoiesis, 16 and specific inhibitors against JAK2 are currently tested in clinical trials and have therapeutic potentials in treating cancer and inflammatory diseases.…”

“…17 In addition, STAT3 activation also drives the expression of antiapoptotic genes, including BCL-X, BCL-2, c-Myc, and survivin, which were prevented by the inhibition of STAT3 signaling. 12,18 Recently, STAT3 activation has been implicated in the enrichment of cancer stem cell-like residue population in isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line after paclitaxel treatment. 19 Of note, persistently activated STAT3 promotes tumor cell proliferation, survival, and invasion via promoting pro-oncogenic pathways including nuclear factor-JB and interleukin-6/GP130/JAK2 signaling and by opposing the STAT1 and nuclear factor-JBYmediated T h 1 antitumor immunity.…”

“…Others have reported that inhibition of JAK2/STAT3 signaling leads to increased cell cycle distribution to G0/G1 phase because of suppression of cyclin D1 expression, which is required for G1 to S phase transition during cell cycle. 12 The differences among these studies might be attributed to the variability of the cell lines studied; nevertheless, targeting JAK2/STAT3 pathway might exert synergistic effects to the proapoptotic effects of paclitaxel treatment.…”

“…8,12 To test whether STAT3 activation was prevented after inhibition of JAK2, we detected the phosphorylation of STAT3 via Western blot analysis. As shown in Figure 5A and B, JAK2-siRNA significantly reduced the level of phosphorylated STAT3 compared with vehicle or nontargeting siRNA.…”

Effect of VTCN1 on progression and metastasis of ovarian carcinoma in vitro and vivo

“…In many tumors, proliferation could be inhibited by the inhibitors of these cell cycle relative proteins [20][21][22]. And JAK2/STAT demonstrated the adjustment effect of proliferation, differentiation, apoptosis migration and immunity in cells according to previous researches [23][24][25][26]. Meanwhile, the results of bioinformatics analysis implied that JAK2/STAT and cell cycle signaling pathways were involved in the regulation caused by VTCN1.…”