PMID- 32033025
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 12
IP  - 2
DP  - 2020 Feb 4
TI  - Inhibition of Wnt/beta-Catenin Signaling in Neuroendocrine Tumors in vitro: 
      Antitumoral Effects.
LID - 10.3390/cancers12020345 [doi]
LID - 345
AB  - BACKGROUND AND AIMS: Inhibition of Wnt/beta-catenin signaling by specific inhibitors 
      is currently being investigated as an antitumoral strategy for various cancers. 
      The role of Wnt/beta-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 beta-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 beta-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/beta-catenin signaling by the dose- and time-dependent downregulation of 
      low-density lipoprotein receptor-related protein 6 (LRP6) phosphorylation and 
      non-phosphorylated beta-catenin and total beta-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 beta-catenin inhibitor PRI-724 caused significant growth 
      inhibition, while the knockdown of beta-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 beta-catenin inhibitor 
      PRI-724 possesses antitumor properties in NET cell lines. Future studies are 
      needed to determine the role of Wnt/beta-catenin signaling in NET as a potential 
      therapeutic target.
FAU - Jin, Xi-Feng
AU  - Jin XF
AD  - Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet 
      Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
FAU - Spoettl, Gerald
AU  - Spoettl G
AD  - Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet 
      Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
FAU - Maurer, Julian
AU  - Maurer J
AD  - Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet 
      Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
FAU - Nolting, Svenja
AU  - Nolting S
AD  - Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet 
      Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
AD  - 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.
FAU - Auernhammer, Christoph Josef
AU  - Auernhammer CJ
AD  - Department of Internal Medicine 4, University-Hospital, Klinikum der Universitaet 
      Muenchen, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20200204
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7072467
OTO - NOTNLM
OT  - Wnt/beta-catenin signaling
OT  - neuroendocrine tumor
OT  - porcupine inhibitor
OT  - beta-catenin inhibitor
OT  - beta-catenin siRNA
COIS- This study has been funded by an unrestricted research grant to C.J.A. from 
      Novartis Pharma GmbH, Nuernberg, Germany. C.J.A. has received research contracts 
      (Ipsen, Novartis, ITM Solucin), lecture honorarium (Ipsen, Novartis, Falk 
      Foundation) and advisory board honorarium (Novartis). S.N. has received research 
      contracts (Novartis) and lecture fees (Ipsen). The other authors declare no 
      conflicts of interest in this work.
EDAT- 2020/02/09 06:00
MHDA- 2020/02/09 06:01
PMCR- 2020/02/04
CRDT- 2020/02/09 06:00
PHST- 2019/12/15 00:00 [received]
PHST- 2020/01/18 00:00 [revised]
PHST- 2020/01/30 00:00 [accepted]
PHST- 2020/02/09 06:00 [entrez]
PHST- 2020/02/09 06:00 [pubmed]
PHST- 2020/02/09 06:01 [medline]
PHST- 2020/02/04 00:00 [pmc-release]
AID - cancers12020345 [pii]
AID - cancers-12-00345 [pii]
AID - 10.3390/cancers12020345 [doi]
PST - epublish
SO  - Cancers (Basel). 2020 Feb 4;12(2):345. doi: 10.3390/cancers12020345.