期刊
CANCER LETTERS
卷 388, 期 -, 页码 64-72出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.11.026
关键词
Wnt; beta-Catenin; OGT; TCF/LEF1; Pancreatic tumor; STIM model
类别
资金
- National Institutes of Health (NIH) [CA124723, CA170946]
- Minneamrita Therapeutics, LLC
beta-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 beta-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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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