Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells

Marije J. Veenstra, Peter M. van Koetsveld, Fadime Dogan, William E. Farrell, Richard A. Feelders, Steven W.J. Lamberts, Wouter W. de Herder, Giovanni Vitale, Leo J. Hofland

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.

Original languageEnglish
Pages (from-to)14791-14802
Number of pages12
JournalOncotarget
Volume9
Issue number19
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Neuroendocrine Cells
Neuroendocrine Tumors
decitabine
Somatostatin
Up-Regulation
Valproic Acid
Histone Code
Epigenomics
Octreotide
Therapeutics
Somatostatin Receptors
Messenger RNA
Tumor Cell Line
Genetic Promoter Regions
Methylation
somatostatin receptor 2
Gene Expression
Genes

Keywords

  • BON-1
  • Epigenetics
  • Pancreatic neuroendocrine tumor
  • QGP-1
  • Somatostatin receptor type 2

ASJC Scopus subject areas

  • Oncology

Cite this

Veenstra, M. J., van Koetsveld, P. M., Dogan, F., Farrell, W. E., Feelders, R. A., Lamberts, S. W. J., ... Hofland, L. J. (2018). Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. Oncotarget, 9(19), 14791-14802. https://doi.org/10.18632/oncotarget.9462

Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. / Veenstra, Marije J.; van Koetsveld, Peter M.; Dogan, Fadime; Farrell, William E.; Feelders, Richard A.; Lamberts, Steven W.J.; de Herder, Wouter W.; Vitale, Giovanni; Hofland, Leo J.

In: Oncotarget, Vol. 9, No. 19, 01.01.2018, p. 14791-14802.

Research output: Contribution to journalArticle

Veenstra, MJ, van Koetsveld, PM, Dogan, F, Farrell, WE, Feelders, RA, Lamberts, SWJ, de Herder, WW, Vitale, G & Hofland, LJ 2018, 'Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells', Oncotarget, vol. 9, no. 19, pp. 14791-14802. https://doi.org/10.18632/oncotarget.9462
Veenstra MJ, van Koetsveld PM, Dogan F, Farrell WE, Feelders RA, Lamberts SWJ et al. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. Oncotarget. 2018 Jan 1;9(19):14791-14802. https://doi.org/10.18632/oncotarget.9462
Veenstra, Marije J. ; van Koetsveld, Peter M. ; Dogan, Fadime ; Farrell, William E. ; Feelders, Richard A. ; Lamberts, Steven W.J. ; de Herder, Wouter W. ; Vitale, Giovanni ; Hofland, Leo J. / Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. In: Oncotarget. 2018 ; Vol. 9, No. 19. pp. 14791-14802.
@article{1463c658cf4842b39c13f7f42677d52d,
title = "Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells",
abstract = "Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.",
keywords = "BON-1, Epigenetics, Pancreatic neuroendocrine tumor, QGP-1, Somatostatin receptor type 2",
author = "Veenstra, {Marije J.} and {van Koetsveld}, {Peter M.} and Fadime Dogan and Farrell, {William E.} and Feelders, {Richard A.} and Lamberts, {Steven W.J.} and {de Herder}, {Wouter W.} and Giovanni Vitale and Hofland, {Leo J.}",
year = "2018",
month = "1",
day = "1",
doi = "10.18632/oncotarget.9462",
language = "English",
volume = "9",
pages = "14791--14802",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "19",

}

TY - JOUR

T1 - Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells

AU - Veenstra, Marije J.

AU - van Koetsveld, Peter M.

AU - Dogan, Fadime

AU - Farrell, William E.

AU - Feelders, Richard A.

AU - Lamberts, Steven W.J.

AU - de Herder, Wouter W.

AU - Vitale, Giovanni

AU - Hofland, Leo J.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.

AB - Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.

KW - BON-1

KW - Epigenetics

KW - Pancreatic neuroendocrine tumor

KW - QGP-1

KW - Somatostatin receptor type 2

UR - http://www.scopus.com/inward/record.url?scp=85027279452&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027279452&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.9462

DO - 10.18632/oncotarget.9462

M3 - Article

VL - 9

SP - 14791

EP - 14802

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 19

ER -