Inhibition of β-catenin signaling suppresses pancreatic tumor growth by disrupting nuclear β-catenin/TCF-1 complex: critical role of STAT-3.

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.

• Authors: Kartick C Pramanik, Neel M Fofaria, Parul Gupta, Alok Ranjan, Sung-Hoon Kim, Sanjay K Srivastava
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 13 Pg. 11561-74 (May 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25869100 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• CTNNB1 protein, human
• Dishevelled Proteins
• Phosphoproteins
• STAT3 Transcription Factor
• STAT3 protein, human
• T Cell Transcription Factor 1
• TCF7 protein, human
• beta Catenin
• Proteasome Endopeptidase Complex
• Capsaicin

Topics

• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Capsaicin (pharmacology)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Dishevelled Proteins
• Dose-Response Relationship, Drug
• Female
• Humans
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Phosphoproteins (antagonists & inhibitors, metabolism)
• Phosphorylation
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis
• STAT3 Transcription Factor (genetics, metabolism)
• T Cell Transcription Factor 1 (genetics, metabolism)
• Time Factors
• Transfection
• Tumor Burden
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays
• beta Catenin (genetics, metabolism)