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.

Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

“…However, whether or not solamargines could affect other phosphorylation sites of Stat3 still remained to be determined. The phosphoryation (Tyr705) of Stat3 was reported to interacted with phosphatidylinositol 3-kinase (PI3-K) - induced oncogenic transformation and growth in both non-cancer and cancer cell types [52-55]. Nevertheless, we reasoned that more experiments are required to further elucidate the true role of Stat3 phosphorylation affected by solamargines.…”

Capsaicin inhibits the Wnt/β-catenin signaling pathway by down-regulating PP2A

“…Since b-catenin and STAT-3, however, crossregulate each other at the transcriptional levels [21,22] and the phosphorylated active form of STAT-3 is required for the nuclear accumulation of b-catenin [23], the reduced level of the phosphorylated STAT-3 in the capsaicin-treated cancer cells might result from its transcriptional down-regulation, which is caused by bcatenin whose level is lowered by capsaicin via a post-translational regulatory mechanism. In line with this possibility, capsaicin could down-regulate further the level of b-catenin even in the presence of STAT-3 inhibitor [20], suggesting a possible action mechanism of capsaicin which does not involve STAT-3. The phosphorylation of PP2A at tyrosine 307 can be enhanced by inhibition of its autodephosphorylation activity [24].…”

“…PP2A plays an essential role for the steady-state levels of b-catenin and Wnt pathway by reversing its phosphorylation mediated by GSK3 and/ or CK1, though it has opposing roles in Wnt signaling depending on the associated regulatory subunits and substrates [6]. A recent study has shown that capsaicin represses b-catenin/Tcf1 signaling by down-regulating the phosphorylation of STAT-3 in pancreatic cancer cells [20]. Since b-catenin and STAT-3, however, crossregulate each other at the transcriptional levels [21,22] and the phosphorylated active form of STAT-3 is required for the nuclear accumulation of b-catenin [23], the reduced level of the phosphorylated STAT-3 in the capsaicin-treated cancer cells might result from its transcriptional down-regulation, which is caused by bcatenin whose level is lowered by capsaicin via a post-translational regulatory mechanism.…”

The Ca2+ mobilisation and the inhibition of akt reduced the binding of PEO-1 cells to fibronectin

“…The inhibition of β-catenin activity causes suppression of several cancer hallmarks, which might be useful as a putative drug target. 34 Pramanik et al 35 found that inhibition of β-catenin signaling blocked pancreatic tumor growth. Verma et al 36 showed that small interfering RNAs directed against β-catenin reduced β-catenin-dependent gene expression and growth of colon cancer cells.…”