Inhibition of β-Catenin signaling suppresses pancreatic tumor growth by disrupting nuclear β-Catenin/TCF-1 complex: Critical role of STAT-3
| Autor: | Sung-Hoon Kim, Neel M. Fofaria, Sanjay K. Srivastava, Parul Gupta, Alok Ranjan, Kartick C. Pramanik |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
STAT3 Transcription Factor
Proteasome Endopeptidase Complex Beta-catenin orthotopic tumor Time Factors β-Catenin pancreatic cancer Dishevelled Proteins Mice Nude Antineoplastic Agents Apoptosis Biology Transfection STAT3 chemistry.chemical_compound Pancreatic cancer Cell Line Tumor medicine T Cell Transcription Factor 1 Animals Humans Phosphorylation Wnt Signaling Pathway beta Catenin Adaptor Proteins Signal Transducing Cell Proliferation Cell Nucleus Dose-Response Relationship Drug GSK-3β Wnt signaling pathway medicine.disease Phosphoproteins Xenograft Model Antitumor Assays Tumor Burden Pancreatic Neoplasms Oncology chemistry Capsaicin Catenin Proteolysis Cancer research biology.protein Female Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Kartick C. Pramanik 1 , Neel M. Fofaria 1 , Parul Gupta 1 , Alok Ranjan 1 , Sung-Hoon Kim 2 , Sanjay K. Srivastava 1, 2 1 Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 2 Cancer Preventive Material Development Research Center, College of Korean Medicine, Department of Pathology, Kyunghee University, Dongdaemun-ku, Seoul 131–701, South Korea Correspondence to: Sanjay K. Srivastava, e-mail: sanjay.srivastava@ttuhsc.edu Sung-Hoon Kim, e-mail: sungkim7@khu.ac.kr Keywords: STAT3, β-catenin, GSK-3β, pancreatic cancer, orthotopic tumor Received: November 26, 2014 Accepted: February 23, 2015 Published: March 21, 2015 ABSTRACT Aberrant activation of β-catenin/TCF signaling is related to the invasiveness of pancreatic cancer. In the present study, we evaluated the effect of capsaicin on β-catenin/TCF signaling. In a concentration and time-dependent study, we observed that capsaicin treatment inhibits the activation of dishevelled (Dsh) protein DvI-1 in L3.6PL, PanC-1 and MiaPaCa-2 pancreatic cancer cells. Capsaicin treatment induced GSK-3β by inhibiting its phosphorylation and further activated APC and Axin multicomplex, leading to the proteasomal degradation of β-catenin. Expression of TCF-1 and β-catenin-responsive proteins, c-Myc and cyclin D1 also decreased in response to capsaicin treatment. Pre-treatment of cells with MG-132 blocked capsaicin-mediated proteasomal degradation of β-catenin. To establish the involvement of β-catenin in capsaicin-induced apoptosis, cells were treated with LiCl or SB415286, inhibitors of GSK-3β. Our results reveal that capsaicin treatment suppressed LiCl or SB415286-mediated activation of β-catenin signaling. Our results further showed that capsaicin blocked nuclear translocation of β-catenin, TCF-1 and p-STAT-3 (Tyr705). The immunoprecipitation results indicated that capsaicin treatment reduced the interaction of β-catenin and TCF-1 in the nucleus. Moreover, capsaicin treatment significantly decreased the phosphorylation of STAT-3 at Tyr705. Interestingly, STAT-3 over expression or STAT-3 activation by IL-6, significantly increased the levels of β-catenin and attenuated the effects of capsaicin in inhibiting β-catenin signaling. Finally, capsaicin mediated inhibition of orthotopic tumor growth was associated with inhibition of β-catenin/TCF-1 signaling. Taken together, our results suggest that capsaicin-induced apoptosis in pancreatic cancer cells was associated with inhibition of β-catenin signaling due to the dissociation of β-catenin/TCF-1 complex and the process was orchestrated by STAT-3. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|