STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma

Oi, Toru; Asanuma, Kunihiro; Matsumine, Akihiko; Matsubara, Takehiro; Nakamura, Tomoki; Iino, Takahiro; Asanuma, Yumiko; Goto, Masayuki; Okuno, Kazuma; Kakimoto, Takuya; Yada, Yuki; Sudo, Akihiro

doi:10.3892/ijo.2016.3757

Cited by 24 publications

(20 citation statements)

References 33 publications

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“…These observations are in agreement with previous reports in osteosarcoma and other cancers, which show that inhibition of STAT3 leads to decreased expression of survivin, VEGF-A, and Bcl-xl. Recently, Oi et al showed that a plant-derived STAT3 inhibitor, cucurbitacin, suppresses the expression of c-myc and survivin proteins [ 31 ]. Also, siRNA-mediated inhibition of STAT3 leads to the downregulation of survivin and VEGF-A in canine osteosarcoma cells [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells

Zuo

Shogren

Zang

et al. 2018

J Exp Clin Cancer Res

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BackgroundOsteosarcoma is the most common bone cancer. Despite advances, molecular mechanisms associated with osteosarcoma have not been fully understood. Hence, an effective treatment for osteosarcoma has yet to be developed. Even though signal transducer and activator of transcription3 (STAT3) has been implicated, its role in pathogenesis of osteosarcoma is not fully determined. In this study, we investigated the antitumor effect of napabucasin (NP) (BBI608), an inhibitor of STAT3 on osteosarcoma in vitro and in vivo and studied the underlying molecular mechanism.MethodsCell viability, colony formation, apoptosis, tumor growth and metastasis assays were performed to examine the effect of NP on osteosarcoma in vitro and in vivo. Real-time RT-PCR, western analysis, immunofluorescence and reporter assays were used to monitor the expression and activity of proteins and underlying molecular pathways. Protein synthesis, co-immunoprecipitation and CAP binding assays were carried out to understand NP-mediated mechanism of actions in osteosarcoma cells.ResultsOur results show that NP treatment decreases cell viability and induces apoptosis in several osteosarcoma cell lines. NP treatment suppresses both expression and phosphorylation of STAT3 in addition to blocking STAT3-mediated transcription and downstream target proteins in osteosarcoma cells. Furthermore, NP inhibits protein synthesis through regulation of the eukaryotic initiation factor 4E (eIF4E) and eIF4E-binding protein 1 (4E-BP1). NP also inhibits the progression of osteosarcoma tumors and metastasis in vivo in an orthotopic tibial model of osteosarcoma.ConclusionsTaken together, our investigation reveals that NP acts through a novel mechanism and inhibits osteosarcoma growth and metastasis, and could be investigated clinically for treating osteosarcoma patients alone or in combination with other drugs.

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Section: Discussionmentioning

confidence: 99%

Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells

Zuo

Shogren

Zang

et al. 2018

J Exp Clin Cancer Res

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“…Chronic lymphocytic leukemia (CLL) remains an incurable disease with an extremely variable course (1,2). It is featured by a dynamic imbalance between the proliferation and apoptosis of leukemia cells and by the accumulation of neoplastic B lymphocytes co-expressing CD5 and CD19 antigens (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia

Chen

et al. 2018

Oncol Rep

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Interleukin‑9 (IL‑9) can function as both a positive and negative regulator of immune response, however the role of IL‑9 in tumor immunity is poorly understood. Chronic lymphocytic leukemia (CLL) is the most common chronic lympho‑proliferative disorder. Twenty CLL patients from 2010 to 2011 were recruited in the study. Expression and phosphorylation of transcription factor STAT3 and differential microRNAs (miRs) in peripheral blood mononuclear cells (PBMCs) from CLL patient samples were analyzed. In a previous study, we found a high level of IL‑9 in CLL patients. Concomitantly, overexpression of pSTAT3, miR‑155, and miR‑21 were observed in PBMCs from CLL patients in the present study. To elucidate whether there was interaction among IL‑9, STAT3, miR‑155, and miR‑21, MEC‑1 cells were used for further study. Our results revealed that there was no detectable IL‑9 in the culture medium of MEC‑1 cells. However, the IL‑9 protein could be detected using western blotting in MEC‑1 cells. Notably, when recombinant human IL‑9 (rIL‑9) was added to the medium of culturing MEC‑1 cells, the expression levels of pSTAT3 and IL‑9 in MEC‑1 cells were increased in a time‑dependent manner, which could be blocked by STAT3 inhibitor. Both miR‑155 and miR‑21 could increase IL‑9 expression, which could also be suppressed by the inhibitor of STAT3. Our data indicated that the existence of the novel 'extracellular IL‑9/pSTAT3/miR‑155/miR‑21/intracellular IL‑9' positive feedback system in CLL cells, provides a novel insight in the pathogenesis and possible therapeutic strategy of CLL.

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“…Literatures have shown that over-expression and aberrant activation of STAT3 contributes to the tumorigenesis, progression, and poor prognosis of several cancers including OS 47–50 . Besides, growing concentrations have focused on novel drugs investigation by treating STAT3 as a therapy target 51–53 . Our study showed that dynasore treatment inhibited cell proliferation, migration, invasion and tumorigenesis of OS, decreased the expression of p -STAT3 in vitro and in xenograft mouse model.…”

Section: Discussionmentioning

confidence: 99%

Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma

Zhong

Shi

et al. 2019

Cell Death Dis

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Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients' health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.

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STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma

Cited by 24 publications

References 33 publications

Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells

Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells

Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia

Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma

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