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Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer

View Article: PubMed Central - PubMed

ABSTRACT

NF-κB plays an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreased overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits NGF mediated and neural-tumor co-culture in vitro invasion and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

No MeSH data available.


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Inhibition of neurotrophic signaling in vivo decreases neural invasion: Minnelide (a) decreased neurotrophin and neurotrophin receptor gene expression in KPC tumors and (b) nerve size and density. In a sciatic nerve invasion model Minnelide prevented nerve destruction as measured by (c) increased paw spread as compared to saline control; (d) decreased primary tumor volume in the sciatic nerve and (e) decreased invasion through the nerve as determined by nerve diameter proximal to the primary tumor site. Each bar is representative of three or more independent experiments; error bars are represented in SEM; and the asterisk (*) indicates a p value < 0.05.
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Figure 6: Inhibition of neurotrophic signaling in vivo decreases neural invasion: Minnelide (a) decreased neurotrophin and neurotrophin receptor gene expression in KPC tumors and (b) nerve size and density. In a sciatic nerve invasion model Minnelide prevented nerve destruction as measured by (c) increased paw spread as compared to saline control; (d) decreased primary tumor volume in the sciatic nerve and (e) decreased invasion through the nerve as determined by nerve diameter proximal to the primary tumor site. Each bar is representative of three or more independent experiments; error bars are represented in SEM; and the asterisk (*) indicates a p value < 0.05.

Mentions: Using the spontaneous pancreatic cancer murine model, KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre transgenic), mice were treated with Minnelide, a pro-drug, water soluble formulation of triptolide. Minnelide treatment decreased expression of neurotrophins ARTN (0.456 fold ± 0.197) and GDNF (0.167 fold ± 0.045) and neurotrophin receptors GRFa3 (0.085 fold ± 0.051), TRKB (0.038 fold ±0.018), TRKA (0.097 fold ± 0.035), NTRp75 (0.244 fold ± 0.133) (Figure 6a). PGP 9.5 staining of the tumors revealed that the thickness and density of intratumoral nerves was decreased (Figure 6b).


Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer
Inhibition of neurotrophic signaling in vivo decreases neural invasion: Minnelide (a) decreased neurotrophin and neurotrophin receptor gene expression in KPC tumors and (b) nerve size and density. In a sciatic nerve invasion model Minnelide prevented nerve destruction as measured by (c) increased paw spread as compared to saline control; (d) decreased primary tumor volume in the sciatic nerve and (e) decreased invasion through the nerve as determined by nerve diameter proximal to the primary tumor site. Each bar is representative of three or more independent experiments; error bars are represented in SEM; and the asterisk (*) indicates a p value < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5121017&req=5

Figure 6: Inhibition of neurotrophic signaling in vivo decreases neural invasion: Minnelide (a) decreased neurotrophin and neurotrophin receptor gene expression in KPC tumors and (b) nerve size and density. In a sciatic nerve invasion model Minnelide prevented nerve destruction as measured by (c) increased paw spread as compared to saline control; (d) decreased primary tumor volume in the sciatic nerve and (e) decreased invasion through the nerve as determined by nerve diameter proximal to the primary tumor site. Each bar is representative of three or more independent experiments; error bars are represented in SEM; and the asterisk (*) indicates a p value < 0.05.
Mentions: Using the spontaneous pancreatic cancer murine model, KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre transgenic), mice were treated with Minnelide, a pro-drug, water soluble formulation of triptolide. Minnelide treatment decreased expression of neurotrophins ARTN (0.456 fold ± 0.197) and GDNF (0.167 fold ± 0.045) and neurotrophin receptors GRFa3 (0.085 fold ± 0.051), TRKB (0.038 fold ±0.018), TRKA (0.097 fold ± 0.035), NTRp75 (0.244 fold ± 0.133) (Figure 6a). PGP 9.5 staining of the tumors revealed that the thickness and density of intratumoral nerves was decreased (Figure 6b).

View Article: PubMed Central - PubMed

ABSTRACT

NF-&kappa;B plays an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study we demonstrate the importance of activated NF-&kappa;B signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-&kappa;B activity was accomplished through the specific NF-&kappa;B inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKB&alpha; repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-&kappa;B decreased the expression of several EMT transcription factors (SNAI1, SNAI2, ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-&kappa;B inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreased overall metastasis. Furthermore, we demonstrate the importance of active NF-&kappa;B signaling in neural invasion. Triptolide treatment inhibits NGF mediated and neural-tumor co-culture in vitro invasion and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-&kappa;B signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

No MeSH data available.


Related in: MedlinePlus