title: Modulation of post-translational modifications in β-catenin and LRP6 inhibits Wnt signaling pathway in pancreatic cancer.
abstract: 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.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Miami, FL, USA.
authors.forename: Bharti
authors.initials: B
authors.lastname: Garg
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Miami, FL, USA.
authors.forename: Bhuwan
authors.initials: B
authors.lastname: Giri
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Miami, FL, USA.
authors.forename: Kaustav
authors.initials: K
authors.lastname: Majumder
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Miami, FL, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Dudeja
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Miami, FL, USA.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Miami, FL, USA. Electronic address: asaluja@miami.edu.
authors.forename: Ashok
authors.initials: A
authors.lastname: Saluja
mesh_terms: D000818:Animals; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin
keywords: OGT; Pancreatic tumor; STIM model; TCF/LEF1; Wnt; β-Catenin