STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma

Abstract

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) regulates the expression of genes that mediate cell survival, proliferation, and angiogenesis and is aberrantly activated in various types of malignancies, including renal cell carcinoma (RCC). We examined whether it could be a novel therapeutic target for RCC by using the STAT3 inhibitor WP1066. METHODS: The antitumour activities and related mechanisms of WP1066 were investigated in vitro on renal cancer cell lines and in vivo on murine xenografts. RESULTS: In Caki-1 and 786-O renal cancer cells, 5 mM WP1066 prevented the phosphorylation of STAT3, and 2.5 mM WP1066 significantly (Po0.01) inhibited cell survival and proliferation. WP1066 suppressed the expression of Bcl-2, induced apoptosis, and inhibited the basal and hypoxia-induced expression of HIF1a and HIF2a, as well as vascular endothelial growth factor secretion into cell culture medium. Human umbilical vascular endothelial cells cocultured with media from WP1066-treated cells showed significantly reduced tubulogenesis (Po0.05). Systemic oral administration of WP1066 to mice for 19 days significantly inhibited the growth of Caki-1 xenograft tumours (Po0.05), and pathological analysis of xenografts of WP1066-treated mice showed decreased immunostaining of phosphorylated STAT3 and reduced length of CD34-positive vessels (Po0.05). CONCLUSIONS: Our results suggest that using WP1066 to inhibit the STAT3 signalling pathway could be a novel therapeutic strategy against RCC.

Cucurbitacin I Induces Protective Autophagy in Glioblastoma in Vitro and in Vivo

“…Further investigation documented that cucurbitacin I treatment inhibited the JAK2/STAT3 pathway, accompanied by decreased levels of HIF-1␣, which echoed the findings that the JAK2/STAT3 pathway positive regulates HIF-1␣ in a variety of cancer cell types (37)(38)(39)(40). HIF-1␣ plays an important role in hypoxia-induced autophagy, requiring specific activation of an autophagy-inducing molecule, BNIP3, which is activated by HIF-1 only in hypoxic cells (53).…”

HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway

“…The results showed that the protein expression and phosphorylation level (Tyr 705) of STAT3 were elevated in U251SC cells (Figure 6a), whereas the phosphorylation at Ser 727 was not detected (data was not shown). Here, we found that pretreatment with WP1066 inactivates STAT3 by blocking its phosphorylation at Tyr705 and inhibits its nuclear translocation 25 or STAT3 siRNA dramatically decreased the mRNA and protein expression of HIF-1a, FABP7, and Hey1 (Figures 6b and c). We also found that PI3K/AKT/mTOR and ERK/MAPK signaling pathways, which have an important role in the translation of HIF-1a protein, were preferentially activated in U251SC (Figure 6a).…”

Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation

“…Persistent STAT3 activation is oncogenic and regulates cell-cycle progression, tumor invasion, metastasis, and angiogenesis (13)(14)(15)(16). Several reports showed that inhibition of STAT3 suppresses the growth of cancer cells and enhances the sensitivity to anticancer drugs in multiple types of cancers (17)(18)(19)(20)(21)(22)(23). Therefore, STAT3 has been considered as a potential target for cancer therapy.…”