Original ArticleModulation of post-translational modifications in β-catenin and LRP6 inhibits Wnt signaling pathway in pancreatic cancer

- LRP6 and FZD1 are important co-regulators of β-catenin transport in pancreatic cancer.
- Triptolide reduced β-catenin transport and its interaction with TCF in nucleus.
- Triptolide abolished LRP6 phosphorylation.
- OGT inhibition reduced β-catenin transport in nucleus.
- Up-regulated WNT pathway is associated with the progression of pancreatic cancer.

β-Catenin/Wnt signaling pathway is critically regulated in a normal cell by a number of post-translational modifications. In pancreatic cancer however, aberrant activation of this pathway plays a significant role in tumor progression and metastasis. Though a number of studies have focused on understanding Wnt signaling pathway in pancreatic cancer, there has been no systematic study to evaluate molecules that may be affecting this pathway. In the current study, we used a diterpene triepoxide, triptolide, to inhibit post-translational modifications in Wnt pathway and evaluated how this compound may be affecting the intricate signaling that regulates cell proliferation in pancreatic cancer.Our results showed that triptolide inhibits the activation of WNT1, FZD1, and disheveled (DSH) in pancreatic cancer cell lines MIA PaCa-2 and S2-VP10 by inhibiting the phosphorylation of LRP6 and simultaneously blocked translocation of β-catenin to the nucleus by inhibiting its glycosylation.Additionally, inhibition of post-translational modification of the Wnt-signaling pathway also demonstrated regression of tumor growth in a Syngenic Tumor Implantation Model (STIM). Interestingly, these findings suggest Wnt signaling is a vital molecular pathway in pancreatic cancer and may be amenable to targeted drug therapy.