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Open AccessArticle

Inhibition of Wnt/β-Catenin Signaling in Neuroendocrine Tumors In Vitro: Antitumoral Effects

1
Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
2
Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Marchioninistr. 15, 81377 Munich, Germany
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(2), 345; https://doi.org/10.3390/cancers12020345
Received: 15 December 2019 / Revised: 18 January 2020 / Accepted: 30 January 2020 / Published: 4 February 2020
(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)
Background and aims: Inhibition of Wnt/β-catenin signaling by specific inhibitors is currently being investigated as an antitumoral strategy for various cancers. The role of Wnt/β-catenin signaling in neuroendocrine tumors still needs to be further investigated. Methods: This study investigated the antitumor activity of the porcupine (PORCN) inhibitor WNT974 and the β-catenin inhibitor PRI-724 in human neuroendocrine tumor (NET) cell lines BON1, QGP-1, and NCI-H727 in vitro. NET cells were treated with WNT974, PRI-724, or small interfering ribonucleic acids against β-catenin, and subsequent analyses included cell viability assays, flow cytometric cell cycle analysis, caspase3/7 assays and Western blot analysis. Results: Treatment of NET cells with WNT974 significantly reduced NET cell viability in a dose- and time-dependent manner by inducing NET cell cycle arrest at the G1 and G2/M phases without inducing apoptosis. WNT974 primarily blocked Wnt/β-catenin signaling by the dose- and time-dependent downregulation of low-density lipoprotein receptor-related protein 6 (LRP6) phosphorylation and non-phosphorylated β-catenin and total β-catenin, as well as the genes targeting the latter (c-Myc and cyclinD1). Furthermore, the WNT974-induced reduction of NET cell viability occurred through the inhibition of GSK-3-dependent or independent signaling (including pAKT/mTOR, pEGFR and pIGFR signaling). Similarly, treatment of NET cells with the β-catenin inhibitor PRI-724 caused significant growth inhibition, while the knockdown of β-catenin expression by siRNA reduced NET tumor cell viability of BON1 cells but not of NCI-H727 cells. Conclusions: The PORCN inhibitor WNT974 possesses antitumor properties in NET cell lines by inhibiting Wnt and related signaling. In addition, the β-catenin inhibitor PRI-724 possesses antitumor properties in NET cell lines. Future studies are needed to determine the role of Wnt/β-catenin signaling in NET as a potential therapeutic target. View Full-Text
Keywords: neuroendocrine tumor; Wnt/β-catenin signaling; porcupine inhibitor; β-catenin inhibitor; β-catenin siRNA neuroendocrine tumor; Wnt/β-catenin signaling; porcupine inhibitor; β-catenin inhibitor; β-catenin siRNA
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Jin, X.-F.; Spöttl, G.; Maurer, J.; Nölting, S.; Auernhammer, C.J. Inhibition of Wnt/β-Catenin Signaling in Neuroendocrine Tumors In Vitro: Antitumoral Effects. Cancers 2020, 12, 345.

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