Bazedoxifene exhibits growth suppressive activity by targeting interleukin-6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma

Autor: Sheng Li, Dan Yan, David Jou, Jiagao Lv, Maocai Zhai, Jiayuh Lin, Lei Tian, Pengcheng Luo, Shengqi Huo, Yina Wang, Jialin Duan, Chongqiang Zhao, Lulu Mageta, Wei Shi, Jingwen Tao, Cuntai Zhang, Li Lin, Chenglong Li, Tianshu Liu, Haiyan Ma, Junyi Guo
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Indoles
Carcinogenesis
Apoptosis
Leukemia Inhibitory Factor
Corrections
Stat3 Signaling Pathway
Mice
0302 clinical medicine
Phosphorylation
STAT3
biology
bazedoxifene
Chemistry
Liver Neoplasms
hepatocellular carcinoma
General Medicine
Hep G2 Cells
Oncology
030220 oncology & carcinogenesis
signal transducer and activator of transcription 3
Original Article
Female
Signal Transduction
STAT3 Transcription Factor
animal structures
Carcinoma
Hepatocellular
Cell Survival
Mice
Nude
03 medical and health sciences
Cell Line
Tumor
Animals
Humans
MTT assay
Viability assay
Cell Proliferation
Glycoproteins
Interleukin-6
Correction
Original Articles
Glycoprotein 130
Receptors
Interleukin-6
Xenograft Model Antitumor Assays
glycoprotein 130
030104 developmental biology
interleukin‐6
biology.protein
STAT protein
Cancer research
Interleukin-4
Leukemia inhibitory factor
Zdroj: Cancer Science
ISSN: 1349-7006
Popis: The interleukin (IL)‐6/glycoprotein (GP)130/signal transducer and activator of transcription (STAT)3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL‐6 binds to IL‐6R, forming a binary complex, which further combines with GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL‐6 and GP130 may inhibit the IL‐6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that bazedoxifene acetate (BAZ), a selective estrogen receptor modulator approved by the US Food and Drug Administration, could inhibit IL‐6/GP130 protein‐protein interactions. Western blot, immunofluorescence staining, wound healing and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V‐FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P‐STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P‐STAT3 induced by IL‐6, but not by leukemia inhibitory factor. BAZ inhibited P‐STAT1 and P‐STAT6 less significantly as elicited by interferon‐α, interferon‐γ and IL‐4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL‐6. BAZ inhibited cell viability, wound healing and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that BAZ inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy.
Databáze: OpenAIRE
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