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.
Highlights
Today pancreatic cancer ranks as the fourth leading cause of cancer related deaths in the United States [1]
Capsaicin treatment further reduced the protein levels of Frizzled, DVI-1, β-catenin, TCF-1, c-Myc and Cyclin D1, while increased glycogen synthase kinase-3β (GSK-3β), adenomatous polyposis coli (APC), and Axin protein levels (Figure 1A, 1B & 1C). These results suggest that capsaicin treatment inhibits the Frizzled receptor, inactivates DSH, resulting in increased APC/Axin/ GSK-3β complex formation, leading to the prevention of β-catenin stabilization and activation of β-catenin/TCF-1 mediated transcriptional responsive genes
We have previously demonstrated that capsaicin-mediated inhibition of pancreatic cancer cells was associated with ROS generation and dissociation of ASK1 and Trx-1complex [32, 33]. β-catenin and other components of Wnt signaling have been found to play an important role in human cancers and that aberrant activation of this signaling pathway was observed in pancreatic tumors [2,3,4]
Summary
Today pancreatic cancer ranks as the fourth leading cause of cancer related deaths in the United States [1]. Β-catenin and other proteins including axin and adenomatous polyposis coli (APC) in the Wnt signaling www.impactjournals.com/oncotarget pathway play an important role in many types of human cancers, including pancreatic cancer [2,3,4]. When Wnt or Frizzled are up-regulated, this complex is inhibited and β-catenin is phosphorylated resulting in its accumulation in the cytoplasm and subsequent nuclear translocation. Β-catenin is stabilized and binds to TCF/LEF transcriptional co-activators, resulting in the up-regulation of transcription responsive genes cyclin D1 and c-Myc. Through regulating target gene expression, β-catenin/TCF signaling is involved in sequential neoplastic development from initiation, progression to metastasis [5, 14,15,16]. Published studies suggest that inhibition of β-catenin decreases TCF transcriptional activity and induces caspase-3-mediated apoptosis [17]
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